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1

Differential regulation of the human 'leukemia inhibitory factor' (LIF) promoter in T47D and MDA-MB 231 breast cancer cells  

Microsoft Academic Search

Leukemia inhibitory factor (LIF) is a pleiotropic inflammatory cytokine. A potential role for LIF in the pathogenesis of human breast cancer was recently indicated by the finding that LIF is produced by MDA-MB 231 breast cancer cells and that it stimulates proliferation of the T47D and MCF-7 breast cancer cell lines. Despite its role as a possible therapeutic target in

Ana-Maria Bamberger; Imke Thuneke; Heinrich M. Schulte

1998-01-01

2

Effects of extremely low-frequency pulsed electromagnetic fields on morphological and biochemical properties of human breast carcinoma cells (T47D).  

PubMed

This study was carried out to investigate the effects of 100 and 217 Hz extremely low-frequency pulsed electromagnetic fields (ELF-PEMF) on cell proliferation, actin reorganization, and ROS generation in a human breast carcinoma cells (T47D). Cells were exposed for 24-72 h, at 100 and 217 Hz, 0.1 mT. The treatment induced a time dependent decrease in cell growth after 72 h and revealed an increase in fluorescence intensity in cytoplasm and actin aggregations around the nucleus as detected by fluorescence microscopy. The amount of actin in T47D cells increased after 48 h exposure to 100 Hz and 24 h to 217 Hz while no changes in nuclear morphology were detected. Exposing the cells to 217 Hz for 72 h caused a dramatically increase of intracellular ROS generation while with exposure to 100 Hz it remained nearly unchanged. These results suggest that exposure to ELF-PEMF (100, 217 Hz, 0.1 mT) are able inducing an increase of actin level, its migration toward nucleus but despite of these changes and dramatically increase in ROS generation the symptoms of apoptosis were not observed. Our results support the hypothesis that cell response to EMF may only be observed at certain window effects; such as frequency and intensity of EMF parameters. PMID:22676212

Sadeghipour, Razmin; Ahmadian, Shahin; Bolouri, Bahram; Pazhang, Yaghub; Shafiezadeh, Mahshid

2012-12-01

3

The Comparison of The Effects of Silybin and Silybin-Phosphatidylcholine on Viability and ESR Expression in Human Breast Cancer T47D Cell Line  

PubMed Central

Objective Silybin is a polyphenol with anti-oxidant and anti-cancer properties. The poor bioavailability of some polyphenols can be improved by binding to phosphatidylcholine. In recent years, studies have been conducted to evaluate the anti-cancer effect of silybin. We studied the effect of silybin and silybin-phosphatidylcholine on ESR1 and ESR2 gene expression and viability in the T47D breast cancer cell line. Materials and Methods In this experimental study, a 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide test (MTT test) was used to determine doses for cell treatment, and the gene expression was analyzed by real-time reverse transcriptase-polymerase chain reaction (real-time RT- PCR). Results Significant dose- and time-dependent cell growth inhibitory effects of silybin and silybin-phosphatidylcholine along with ESR1 down-regulation were observed in T47D cells. In contrast to ESR1, the T47D cell line showed negligible ESR2 expression. Conclusion This study suggests that silybin and silybin-phosphatidylcholine down-regulate ESR1 in ER+breast cancers. Results also show that in the T47D cell line, silybindown-regulation of ESR1 compared with silybin. PMID:25383329

Mahmoodi, Narges; Motamed, Nasrin; Paylakhi, Seyed Hassan

2014-01-01

4

Effects of cadmium on estrogen receptor mediated signaling and estrogen induced DNA synthesis in T47D human breast cancer cells.  

PubMed

Cadmium (Cd) has been shown to bind to the human estrogen receptor (ER), yet studies on Cd's estrogenic effects have yielded inconsistent results. In this study, we investigated the effects of Cd on DNA synthesis and its simultaneous effects on both genomic (mediated by nuclear ER (nER)) and non-genomic (mediated by membrane-bound ER (mER)) signaling in human breast cancer derived T47D cells. No effects on DNA synthesis were observed for non-cytotoxic concentrations of CdCl(2) (0.1-1000 nM), and Cd did not increase progesterone receptor (PgR) or pS2 mRNA levels. However, Cd stimulated phosphorylation of ERK1/2 MAPK, detectable following 10 min and 18 h of treatment. The sustained Cd-induced ERK1/2 phosphorylation was inhibited by the ER antagonist ICI 182,780, suggesting the involvement of ER. In addition, Cd enhanced DNA synthesis and pS2 mRNA levels in estrogen (10 pM estradiol) treated T47D cells. The MEK1/2 specific inhibitor U0126 blocked DNA synthesis stimulated by estradiol (E2) and the E2-Cd mixtures. These findings indicate that the ERK1/2 signaling is critical in E2-related DNA synthesis. The sustained ERK1/2 phosphorylation may contribute to the Cd-induced enhancement of DNA synthesis and pS2 mRNA in mixture with low-concentration E2. PMID:19041697

Zang, Yu; Odwin-Dacosta, Shelly; Yager, James D

2009-01-30

5

Growth Hormone Signaling in Human T47D Breast Cancer Cells: Potential Role for a Growth Hormone Receptor-Prolactin Receptor Complex  

PubMed Central

GH receptor (GHR) and prolactin (PRL) receptor (PRLR) are structurally similar cytokine receptor superfamily members that are highly conserved among species. GH has growth-promoting and metabolic effects in various tissues in vertebrates, including humans. PRL is essential for regulation of lactation in mammals. Recent studies indicate that breast tissue bears GHR and PRLR and that both GH and PRL may impact development or behavior of breast cancer cells. An important facet of human GH (hGH) and human PRL (hPRL) biology is that although hPRL interacts only with hPRLR, hGH binds well to both hGHR and hPRLR. Presently, we investigated potential signaling effects of both hormones in the estrogen receptor- and progesterone receptor-positive human T47D breast cancer cell line. We found that this cell type expresses ample GHR and PRLR and responds well to both hGH and hPRL, as evidenced by activation of the Janus kinase 2/signal transducer and activator of transcription 5 pathway. Immunoprecipitation studies revealed specific GHR-PRLR association in these cells that was acutely enhanced by GH treatment. Although GH caused formation of disulfide-linked and chemically cross-linked GHR dimers in T47D cells, GH preferentially induced tyrosine phosphorylation of PRLR rather than GHR. Notably, both a GHR-specific ligand antagonist (B2036) and a GHR-specific antagonist monoclonal antibody (anti-GHRext-mAb) failed to inhibit GH-induced signal transducer and activator of transcription 5 activation. In contrast, although the non-GHR-specific GH antagonist (G120R) and the PRL antagonist (G129R) individually only partially inhibited GH-induced activation, combined treatment with these two antagonists conferred greater inhibition than either alone. These data indicate that endogenous GHR and PRLR associate (possibly as a GHR-PRLR heterodimer) in human breast cancer cells and that GH signaling in these cells is largely mediated by the PRLR in the context of both PRLR-PRLR homodimers and GHR-PRLR heterodimers, broadening our understanding of how these related hormones and their related receptors may function in physiology and pathophysiology. PMID:21310852

Xu, Jie; Zhang, Yue; Berry, Philip A.; Jiang, Jing; Lobie, Peter E.; Langenheim, John F.; Chen, Wen Y.

2011-01-01

6

Induction of ROS formation, poly(ADP-ribose) polymerase-1 activation, and cell death by PCB126 and PCB153 in human T47D and MDA-MB-231 breast cancer cells.  

PubMed

The primary purpose of this research is to investigate whether exposure to polychlorinated biphenyls (PCBs), i.e. PCB153 and PCB126, is associated with induction of reactive oxygen species (ROS), poly(ADP-ribose) polymerase-1 (PARP-1) activation, and cell death in human T47D and MDA-MB-231 breast cancer cells. Results indicated that PCB153 and PCB126 induced concentration- and time-dependent increases in cytotoxic response and ROS formation in both T47D and MDA-MB-231 cells. At non-cytotoxic concentrations both PCB153 and PCB126 induced decreases in intracellular NAD(P)H and NAD+ in T47D and MDA-MB-231 cells where T47D cells were more resistant to PCB-induced reduction in intracellular NAD(P)H than MDA-MB-231 cells. Further investigation indicated that three specific PARP inhibitors completely blocked PCB-induced decreases in intracellular NAD(P)H in both T47D and MDA-MB-231 cells. These results imply that decreases in intracellular NAD(P)H in PCB-treated cells may be, in part, due to depletion of intracellular NAD+ pool mediated by PARP-1 activation through formation of DNA strand breaks. Overall, the extent of cytotoxic response, ROS formation, and PARP-1 activation generated in T47D and MDA-MB-231 cells was greater for PCB153 than for PCB126. In addition, the cytotoxicity induced by PCB153 and PCB126 in both T47D and MDA-MB-231 cells was completely blocked by co-treatment of catalase, dimethylsulfoxide, cupper (I)-/iron (II)-specific chelators, and CYP1A/2B inhibitors. This evidence suggests the involvement of ROS, Cu(I), Fe(II), and CYP1A/2B enzymes in mediating the induction of cell death by PCB153 and PCB126. Further, antagonism was observed between PCB126 and PCB153 for effects on cytotoxic response and ROS formation in T47D and MDA-MB-231 cells. Antagonism was also observed between PCB153 and PCB126 in the induction of NAD(P)H depletion at lower concentration (<10 microM) in T47D cells, but not in MDA-MB-231 cells. In conclusions, results from our investigation suggest that ROS formation induced by PCBs is a significant determinant factor in mediating the DNA damage and cell death in human breast cancer cells. The data also suggests that the status of estrogen receptor alpha may play a role in modulating the PCB-induced oxidative DNA damage and cell death in human breast cancer cells. PMID:16884709

Lin, Chia-Hua; Lin, Po-Hsiung

2006-08-25

7

Induction of CYP1A1 and CYP1B1 by benzo(k)fluoranthene and benzo(a)pyrene in T-47D human breast cancer cells: Roles of PAH interactions and PAH metabolites  

SciTech Connect

The interactions of polycyclic aromatic hydrocarbons (PAH) and cytochromes P450 (CYP) are complex; PAHs are enzyme inducers, substrates, and inhibitors. In T-47D breast cancer cells, exposure to 0.1 to 1 {mu}M benzo(k)fluoranthene (BKF) induced CYP1A1/1B1-catalyzed 17{beta}-estradiol (E{sub 2}) metabolism, whereas BKF levels greater than 1 {mu}M inhibited E{sub 2} metabolism. Time course studies showed that induction of CYP1-catalyzed E{sub 2} metabolism persisted after the disappearance of BKF or co-exposed benzo(a)pyrene, suggesting that BKF metabolites retaining Ah receptor agonist activity were responsible for prolonged CYP1 induction. BKF metabolites were shown, through the use of ethoxyresorufin O-deethylase and CYP1A1-promoter-luciferase reporter assays to induce CYP1A1/1B1 in T-47D cells. Metabolites formed by oxidation at the C-2/C-3 region of BKF had potencies for CYP1 induction exceeding those of BKF, whereas C-8/C-9 oxidative metabolites were somewhat less potent than BKF. The activities of expressed human CYP1A1 and 1B1 with BKF as substrate were investigated by use of HPLC with fluorescence detection, and by GC/MS. The results showed that both enzymes efficiently catalyzed the formation of 3-, 8-, and 9-OHBKF from BKF. These studies indicate that the inductive effects of PAH metabolites as potent CYP1 inducers are likely to be additional important factors in PAH-CYP interactions that affect metabolism and bioactivation of other PAHs, ultimately modulating PAH toxicity and carcinogenicity.

Spink, David C. [Wadsworth Center, New York State Department of Health, Albany, NY 12201-0509 (United States)], E-mail: spink@wadsworth.org; Wu, Susan J.; Spink, Barbara C.; Hussain, Mirza M.; Vakharia, Dilip D.; Pentecost, Brian T.; Kaminsky, Laurence S. [Wadsworth Center, New York State Department of Health, Albany, NY 12201-0509 (United States)

2008-02-01

8

Progesterone-specific stimulation of triglyceride biosynthesis in a breast cancer cell line (T-47D)  

SciTech Connect

The purpose of this study was to examine the lactogenic response of human mammary cancer cell lines to hormones in vitro. Progesterone was found to stimulate the incorporation of 14C from (14C)acetate into triglycerides (TG) and to promote accumulation of TG with a fatty acid composition similar to that of human milk fat in T-47D cells. Lipid droplets were observed in larger numbers without concomitant accumulation of casein granules in cells incubated with progesterone, but secretion of lipid into the medium did not occur. An effect of progesterone on TG accumulation was detectable after 12 hr and was maximal at 72 hr. Increasing doses of progesterone (10(-9) to 10(-5) M) caused a progressive increase in TG accumulation. The presence of cortisol and/or prolactin did not alter TG formation nor the dose response of the cells to progesterone. The growth rate of T-47D cells was not altered by the presence of progesterone in the medium. Neither of the human mammary cancer cell lines, MCF-7 and HBL-100, nor the human fibroblast cell lines, 28 and 857, responded to progesterone. The data indicate that, while the normally lactogenic hormones do not stimulate milk product biosynthesis in the cell lines tested, progesterone specifically stimulated synthesis and accumulation of TG in the T-47D cells.

Judge, S.M.; Chatterton, R.T. Jr.

1983-09-01

9

Cytotoxic Activities of Silver Nanoparticles and Silver Ions in Parent and Tamoxifen-Resistant T47D Human Breast Cancer Cells and Their Combination Effects with Tamoxifen against Resistant Cells  

PubMed Central

Studies on biomedical applications of nanoparticles are growing with a rapid pace. In medicine, nanoparticles may be the solution for multi-drug-resistance which is still a major drawback in chemotherapy of cancer. In the present study, we investigated the potential cytotoxic effect of silver nanoparticles (Ag NPs) and silver ions (Ag+) in both parent and tamoxifen-resistant T47D cells in presence and absence of tamoxifen. Ag NPs were synthesized (< 28 nm) and MTT assay was carried out. The associated IC50 values were found to be: 6.31 µg/ml for Ag NPs/parent cells, 37.06 µg/ml for Ag NPs/tamoxifen-resistant cells, 33.06 µg/ml for Ag+/parent cells and 10.10 µg/ml for Ag+/resistant cells. As a separate experiment, the effect of subinhibitory concentrations of Ag NPs and Ag+ on the proliferation of tamoxifen-resistant cells was evaluated at non-toxic concentrations of tamoxifen. Our results suggested that in non-cytotoxic concentrations of silver nanomaterials and tamoxifen, the combinations of Ag+-tamoxifen and Ag NPs-tamoxifen are still cytotoxic. This finding may be of great potential benefit in chemotherapy of breast cancer; since much lower doses of tamoxifen may be needed to produce the same cytotoxic effect and side effects will be reduced. PMID:23408729

Ostad, Seyed Naser; Dehnad, Shahrzad; Nazari, Zeinab Esmail; Fini, Shohreh Tavajohi; Mokhtari, Narges; Shakibaie, Mojtaba; Shahverdi, Ahmad Reza

2010-01-01

10

Thiolated chitosan nanoparticles as a delivery system for antisense therapy: evaluation against EGFR in T47D breast cancer cells  

PubMed Central

Thiolated chitosan has high transfection and mucoadhesive properties. We investigated the potential of two recently synthesized polymers: NAC-C (N-acetyl cysteine-chitosan) and NAP-C (N-acetyl penicillamine-chitosan) in anticancer drug delivery targeting epidermal growth factor receptor (EGFR). Doxorubicin (DOX) and antisense oligonucleotide (ASOND)-loaded polymer nanoparticles were prepared in water by a gelation process. Particle characterization, drug loading, and drug release were evaluated. To verify drug delivery efficiency in vitro experiments on a breast cancer cell line (T47D) were performed. EGFR gene and protein expression was analyzed by real time quantitative polymerase chain reaction and Western blotting, respectively. A loading percentage of 63% ± 5% for ASOND and 70% ± 5% for DOX was achieved. Drug release data after 15 hours showed that ASOND and DOX were completely released from chitosan-based particles while a lower and more sustained release of only 22% ± 8% was measured for thiolated particles. In a cytosol simulated release medium/reducing environment, such as found intracellularly, polymer-based nanoparticles dissociated, liberating approximately 50% of both active substances within 7 hours. ASOND-loaded polymer nanoparticles had higher stability and high mucoadhesive properties. The ASOND-loaded thiolated particles significantly suppressed EGFR gene expression in T47D cells compared with ASOND-loaded chitosan particles and downregulated EGFR protein expression in cells. This study could facilitate future investigations into the functionality of NAP-C and NAC-C polymers as an efficient ASOND delivery system in vitro and in vivo. PMID:21976973

Talaei, Fatemeh; Azizi, Ebrahim; Dinarvand, Rassoul; Atyabi, Fatemeh

2011-01-01

11

Enhancing the Effects of Low Dose Doxorubicin Treatment by the Radiation in T47D and SKBR3 Breast Cancer Cells  

PubMed Central

Purpose Breast cancer is the most common malignancy of women worldwide. Radiotherapy consists of a vital element in the treatment of breast cancer but relative side effects and different radioactive responses are limiting factors for a successful treatment. Doxorubicin has been used to treat cancers for over 30 years and is considered as the most effective drug in the treatment of breast cancer. There are also many chronic side effects that limit the amount of doxorubicin that can be administered. The combined radio-drug treatment, with low doses, can be an approach for reducing side effects from single modality treatments instead of suitable cure rates. Methods We have studied the effect of 1, 1.5, and 2 Gy doses of 9 MV X-rays along with 1 µM doxorubicin on inducing cell death, apoptosis and also p53 and PTEN gene expression in T47D and SKBR3 breast cancer cells. Results Doxorubicin treatment resulted in upregulation of radiation-induced levels of p53 and downregulation of PTEN at 1 and 1.5 Gy in T47D breast cancer cells, as well as downregulation of p53 mRNA level of expression and upregulation of PTEN mRNA level of expression in SKBR3 breast cancer cell line. In addition, doxorubicin in combination with radiation decreased the viability of breast cancer cell lines in the both cell lines. Conclusion Low doses of doxorubicin, with least cell toxicity, may be an effective treatment for breast cancer when used in conjunction with ionizing radiation. PMID:23843848

Aghaee, Fahimeh; Baradaran, Behzad; Mesbahi, Asghar; Mohammadzadeh, Mohammad; Jafarabadi, Mohammad Asghari

2013-01-01

12

Identification of novel proteins induced by estradiol, 4-hydroxytamoxifen and acolbifene in T47D breast cancer cells  

Microsoft Academic Search

Tamoxifen is currently used as adjuvant therapy for estrogen receptor (ER) positive breast cancer patients and as a chemopreventative agent. Although ER is a predictive marker for tamoxifen response, ER status fails to predict tamoxifen response in a significant number of patients highlighting the need to identify new pathways for tamoxifen sensitivity\\/resistance. To identify novel proteins induced by tamoxifen in

Mariam H. Al-Dhaheri; Yatrik M. Shah; Venkatesha Basrur; Steven Pind; Brian G. Rowan

2006-01-01

13

Effect of nomegestrol acetate on estrogen biosynthesis and transformation in MCF7 and T47-D breast cancer cells  

Microsoft Academic Search

Although ovaries serve as the primary source of estrogen for pre-menopausal women, after menopause estrogen biosynthesis from circulating precursors occurs in peripheral tissues by the action of several enzymes, 17?-hydroxysteroid dehydrogenase 1 (17?-HSD1), aromatase and estrogen sulfatase. In the breast, both normal and tumoral tissues have been shown to be capable of synthesizing estrogens, and this local estrogen production can

J. Shields-Botella; G. Chetrite; S. Meschi; J. R. Pasqualini

2005-01-01

14

Stable overexpression of DNA fragmentation factor in T-47D cells: sensitization of breast cancer cells to apoptosis in response to acetazolamide and sulfabenzamide.  

PubMed

Alterations in expression of the DFF40 gene have been reported in some cancers. This study is an in vitro study of the therapeutic effects of gene transfer that lead to elevation in DFF40 expression within T-47D cells in the presence of sulfonamide drugs. In this study, we have constructed a eukaryotic expression vector for DFF40 and transfected it into T-47D cancer cells. We used real time RT-PCR to detect the expression of DFF40 and the MTT assay to determine effects of the sulfonamide drugs acetazolamide, sulfabenzamide, sulfathiazole and sulfacetamide on cell viability in the presence of increased and normal DFF40 levels. Cell cycle distribution was assessed by propidium iodide (PI) staining and the rates of apoptosis by annexin V/PI staining. The DNA laddering analysis was employed to evaluate apoptosis. We observed that overexpression of DFF40 was only effective in decreasing viability in cells incubated with acetazolamide and sulfabenzamide. There was enhanced apoptosis in these groups, particularly with acetazolamide. The cell cycle distribution analysis showed that in the presence of sulfonamide drugs there were no substantial changes in empty-vector or DFF40-transfected cells, except for those cells treated with sulfabenzamide or sulfathiazole. There was no DNA laddering in cells that expressed the empty vector when incubated with sulfonamide drugs. In contrast, we observed DNA laddering in cells that expressed DFF40 in the presence of acetazolamide. Our results have demonstrated that combinatorial use of some sulfonamides such as acetazolamide along with increased expression of DFF40 can potently kill tumor cells via apoptosis and may be beneficial for treatment of some chemoresistant cancers. PMID:25086620

Bagheri, Fatemeh; Safarian, Shahrokh; Eslaminejad, Mohamadreza Baghaban; Sheibani, Nader

2014-11-01

15

Prolactin and estradiol utilize distinct mechanisms to increase serine-118 phosphorylation and decrease levels of estrogen receptor alpha in T47D breast cancer cells.  

PubMed

Potential interactions between prolactin (PRL) and estradiol (E2) in breast cancer cells were explored by examining the effect of PRL on estrogen receptor (ER) serine-118 phosphorylation, ER down-regulation, and E2-stimulated cell proliferation. Both E2 and PRL resulted in prolonged ERalpha serine-118 phosphorylation, but used different signaling pathways to achieve this end. Both hormones also decreased the amount of ERalpha, but the mechanisms were different: for E2, the decrease was rapid and resulted from proteasomic degradation, whereas for PRL the decrease was slow and resulted from an effect on levels of ERalpha mRNA. PRL alone had no effect on cell number, but enhanced the increase in number in response to E2. These results are the first to demonstrate similar effects of PRL and E2 on parameters considered key to E2's effects. This suggests heretofore unrecognized and potentially important interactions between these two hormones in the natural history of breast cancer. PMID:19377875

Chen, Yenhao; Huang, Kuangtzu; Chen, Kuanhui E; Walker, Ameae M

2010-04-01

16

Increased Expression of Prolactin Receptor Gene Assessed by Quantitative Polymerase Chain Reaction in Human Breast Tumors Versus Normal Breast Tissues  

Microsoft Academic Search

The role of PRL in human breast tumorigenesis is not well under- stood. One of the limitations is the difficulty of accurately measuring PRL receptors (PRLR) in human tissues. We established a quanti- tative PCR method (Q-PCR) in T-47D human breast cancer cells and applied it to 29 patients, 25 of whom presented with either cancer or fibroadenoma. Four patients

PHILIPPE TOURAINE; JEAN-FRANCOIS MARTINI; BRIGITTE ZAFRANI; JEAN-CLAUDE DURAND; FRANCOISE LABAILLE; CATHERINE MALET; CHRISTINE TRIVIN; MARIE-CATHERINE POSTEL-VINAY; FREDERIQUE KUTTENN; PAUL A. KELLY

2009-01-01

17

ANTICANCER MEDICINAL PLANT, Epipremnum pinnatum (L.) Engl. CHLOROFORM EXTRACTS ELICITED BOTH APOPTOTIC AND NON-APOPTOTIC CELL DEATHS IN T- 47D MAMMARY CARCINOMA CELLS  

Microsoft Academic Search

Epipremnum pinnatum (L.) Engl. chloroform extract produced significant growth inhibition against T-47D breast carcinoma cells and analysis of cell death mechanisms indicated that the extract elicited both apoptotic and non-apoptotic programmed cell deaths. T-47D cells exposed to the extract produced a significant up-regulation of c-myc and caspase-3 mRNA expression levels as compared to untreated cells. The up-regulation of caspase-3 mRNA

Tan Mei Lan; Shaida Fariza Sulaiman; Nazalan Najimudin

18

Mouse Mammary Tumor Virus Chromatin in Human Breast Cancer Cells Is Constitutively Hypersensitive and Exhibits Steroid Hormone-Independent Loading of Transcription Factors In Vivo  

Microsoft Academic Search

We have stably introduced a reporter gene under the control of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR) into human T47D breast cancer cells to study the action of the progesterone receptor (PR) on transcription from a chromatin template. Unexpectedly, the chromatin organization of the MMTV LTR in these human breast cancer cells differed markedly from what

JOE S. MYMRYK; DIANA BERARD; GORDON L. HAGER; ANDTREVOR K. ARCHER

19

p53-dependent inhibition of progestin-induced VEGF expression in human breast cancer cells  

Microsoft Academic Search

VEGF, a potent angiogenic growth factor, is up-regulated in many tumors including human breast tumors and stimulates growth of vascular networks that support tumor growth and metastasis. We previously reported that natural and synthetic progestins (P) increased VEGF mRNA and protein levels in progesterone receptor (PR) containing T47-D human breast cancer cells in a PR dependent manner, but not in

Yayun Liang; Jianbo Wu; George M. Stancel; Salman M. Hyder

2005-01-01

20

METABOLITES OF BENZO[A]FLUORANTHENE ARE POTENT CYP1 INDUCERS IN T-47D HUMAN BREAST CANCER CELLS. (R827180)  

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

21

Evaluation of anticancer effects of newly synthesized dihydropyridine derivatives in comparison to verapamil and doxorubicin on T47D parental and resistant cell lines in vitro.  

PubMed

Failure of current anticancer drugs mandates screening for new compounds of synthetic or biological origin to be used in cancer therapy. Multidrug resistance (MDR) is one of the main obstacles in the chemotherapy of cancer. Efflux of cytotoxic agents mediated by P-glycoprotein (P-gp or MDR1) is believed to be an important mechanism of multidrug resistance. Therefore, we decided to investigate the antiproliferative effects of seven newly synthesized 1,4-dihydropyridine (DHP) derivatives in comparison to verapamil (VP) and doxorubicin (DOX) on human breast cancer T47D cells and its MDR1 overexpressed and moderately resistant cells (RS cells) using MTT cytotoxicity assay. We also examined the effects of these compounds on cytotoxicity of DOX in these two cell types. The cytotoxicity assays using MTT showed that most of the tested new DHP derivatives and VP at 10 microM concentration had varying levels of toxicity on both T47D and RS cells. The toxicity was mostly in the range of 10-25%. However, the cytotoxicity of these DHP derivatives, similar to VP, was significantly less than DOX when comparing IC(50) values. Furthermore, these compounds in general had relatively more cytotoxicity on T47D vs RS cells at 10-microM concentration. Among new DHPs, compounds 7a (3,5-dibenzoyl-4-(2-methylthiazol-4-yl)-1,4-dihydro-2,6-dimethylpyridine) and 7d (3,5-diacetyl-4-[2-(2-chlorophenyl)thiazol-4-yl)]-1,4-dihydro-2,6-dimethylpyridine) showed noticeable potentiation of DOX cytotoxicity (reduction of DOX IC(50)) compared to DOX alone in both cells, particularly in RS cells. This effect was similar to that of VP, a known prototype of MDR1 reversal agent. In other words, compounds 7a and 7d resensitized RS cells to DOX or reversed their resistance. Results indicate that compound 7d exerts highest effect on RS cells. Therefore, these two newly synthesized DHP derivatives, compounds 7a and 7d, are promising as potential new MDR1 reversal agents and should be further studied on other highly resistant cells due to MDR1 overexpression and with further molecular investigation. PMID:17805981

Bazargan, L; Fouladdel, S; Shafiee, A; Amini, M; Ghaffari, S M; Azizi, E

2008-04-01

22

The expression of growth hormone-releasing hormone (GHRH) and its receptor splice variants in human breast cancer lines; the evaluation of signaling mechanisms in the stimulation of cell proliferation.  

PubMed

Antagonists of growth hormone-releasing hormone (GHRH) inhibit growth of various human cancers including breast cancer, xenografted into nude mice or cultured in vitro. Splice variants (SVs) of receptors for GHRH have been found in several human cancers and cancer cell lines. The antiproliferative actions of GHRH antagonists could be mediated in part through these SVs of GHRH receptors. In this study we examined the expression of mRNA for GHRH and SVs of its receptors in human breast cancer cell lines MCF-7, MCF-7MIII, MDA-MB-231, MDA-MB-435, MDA-MB-468, and T47D. mRNA for GHRH was present in all lines tested. mRNA for SV1 isoform of GHRH receptors was found in MCF-7MIII, MDA-MB-468, and T47D; and for SV2 isoform in MCF-7MIII and T47D cell lines. In proliferation studies in vitro, the growth of T47D cells was stimulated by GHRH and dose-dependently inhibited by GHRH antagonist JV-1-38. H89 (protein kinase A inhibitor), bisindolylmaleimide I (protein kinase C [PKC] inhibitor) and verapamil (voltage-dependent calcium channel blocker) inhibited the GHRH-stimulated proliferation of T47D cells. The GHRH antagonist JV-1-38 suppressed the T47D cell growth in vitro stimulated by PKC activator (phorbol-12-myristate-13-acetate). The stimulation of T47D cells by GHRH was followed by an increase in cAMP production and GHRH antagonist JV-1-38 competitively inhibited this effect. Our results suggest that SVs of GHRH receptors could mediate the responses to GHRH and GHRH antagonists in breast cancer through Ca2+-, cAMP- and PKC-dependent mechanisms. The presence of SV1 of GHRH receptors in human cancers provides a rationale for antitumor therapy based on the blockade of this receptor by specific GHRH antagonists. PMID:12602901

Garcia-Fernandez, M Olga; Schally, Andrew V; Varga, Jozsef L; Groot, Kate; Busto, Rebeca

2003-01-01

23

A peptide derived from -fetoprotein prevents the growth of estrogen-dependent human breast cancers sensitive and resistant to tamoxifen  

Microsoft Academic Search

An 8-mer peptide (EMTOVNOG) derived from -fetoprotein was compared with tamoxifen for activity against growth of human breast cancer xenografts implanted in immune-deficient mice. Both peptide and tamoxifen prevented growth of estrogen-receptor-positive MCF-7 and T47D human breast cancer xenografts. A subline of MCF-7, made resistant to tamoxifen by a 6-month exposure to this drug in culture, was found to be

James A. Bennett; Fassil B. Mesfin; Thomas T. Andersen; John F. Gierthy; Herbert I. Jacobson

2002-01-01

24

Glucocorticoids and androgens up-regulate the Zn-? 2 -glycoprotein messenger RNA in human breast cancer cells  

Microsoft Academic Search

We have studied the hormonal regulation of the gene encoding Zn-a2-glycoprotein (Zn-a2-gp), a human protein with a high degree of amino acid sequence similarity to class I histocompatibility antigens that is produced by a specific subset of breast carcinomas. Northern blot analysis revealed that dexamethasone and 5a-dihydrotestosterone strongly induced the accumulation of Zn-a2-gp mRNA in T-47D human breast cancer cells.

Yolanda S. López-Boado; Irene Díez-Itza; Jorge Tolivia; Carlos López-Otín

1994-01-01

25

Death Inducing and Cytoprotective Autophagy in T-47D Cells by Two Common Antibacterial Drugs: Sulfathiazole and Sulfacetamide  

PubMed Central

The broad spectrum of the pharmacological effects of sulfonamide family of drugs motivated us to investigate the cellular mechanisms for anti-cancer effects of sulfathiazole and sulfacetamide on T-47D breast cancer cells. Fluorescent microscopy, flow cytometric analysis, caspase-3 activity and DNA fragmentation assays were used to detect apoptosis. The distribution of the cells among different phases of the cell cycle was measured by flow cytometry. The expression of several genes with important roles in some critical cellular pathways including apoptosis, mTOR/AKT pathway and autophagy were determined by real time RT-PCR analysis. Sulfathiazole and sulfacetamide induced anti-proliferative effects on T-47D cells were independent of apoptosis and cell cycle arrest. The overexpression of critical genes involved in autophagy including ATG5, p53 and DRAM indicated that the main effect of the drug-induced anti-proliferative effects was through induction of autophagy. This process was induced in 2 different forms, including death inducing and cytoprotective autophagy. Sulfathiazole treatment was followed by higher expression of p53/DRAM and downregulation of Akt/ mTOR pathway resulting in death autophagy. In contrast, sulfacetamide treatment lowered expression of p53/DRAM pathway in parallel with upregulation of Akt/mTOR pathway promoting cytoprotective autophagy. The results indicated that autophagy is the main mechanism mediating the anti-cancer effects of sulfathiazole and sulfacetamide on T-47D cells. Alignment of the p53 and DRAM expression along with activation level of Akt survival pathway therefore determines the type of autophagy that occurs. PMID:23450781

Mohammadpour, Raziye; Safarian, Shahrokh; Sheibani, Nader; Norouzi, Saeed; Razazan, Atefeh

2013-01-01

26

Structure-dependent Induction of Aryl Hydrocarbon Hydroxylase in Human Breast Cancer Cell Lines and Characterization of the Ah Receptor1  

Microsoft Academic Search

The structure-dependent induction of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase by 2,3,7,8-tetrachlorodibenzo- p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, and 1,2,4,7,8-pentachlorodi- benzo-p-dioxin was determined in the MCF-7, T47-D, and MDA-MB- 231 human breast cancer cell lines. Both the MCF-7 and T47-D cells were responsive to the induction effects of the halogenated aryl hydro carbons and the structure-induction relationships were comparable to the reported structure-activity

M. Harris; J. Piskorska-Pliszczynska; T. Zacharewski; M. Romkes; S. Safe

27

Role of thrombin in the proliferative response of T-47D mammary tumor cells  

SciTech Connect

The growth of the human metastatic cell line (T-47D) in a chemically defined medium (DM) is shown to be dependent on the presence of three traditional growth factors: epidermal growth factor, insulin, and transferrin. The addition of thrombin further stimulates its growth. The mitogenic action on a human mammary tumor cell lines from epithelial origin is a novel action of thrombin. Cells in the DM show striking morphological changes which are dramatically enhanced by the addition of thrombin. These observations are part of a pleiotropic response to the growth factors: the protein content of the cells increases in the defined medium; the 2DG gels of the {sup 35}S- and {sup 35}P-labeled proteins show important changes in spots, several of which are probably of cytoskeletal origin. It is also shown that cells in a semisolid growth factor-supplemented medium have growth advantages over their counterparts grown with serum. All the phenotypic changes mentioned above reveal the important role of growth factors in the growth and behavior of this mammary cell line. The results obtained with thrombin indicate a new site of action of this enzyme which may be important in the metastatic spread of human mammary tumor cells.

Medrano, E.E.; Cafferata, E.G.A.; Larcher, F. (Instituto de Investigaciones Bioquimicas Fundacion Campomar, Buenos Aires (Argentina) Comision Nacional de Energia Atomica, Buenos Aires (Argentina))

1987-10-01

28

Runx2 Controls a Feed-forward loop between Androgen and Prolactin-induced Protein (PIP) in Stimulating T47D Cell Proliferation  

PubMed Central

PIP is a small polypeptide expressed by breast and prostate cancer (BCa, PCa) cells. However, both the regulation of PIP expression and its function in cancer cells are poorly understood. Using breast and prostate cancer cells, we found that Runx2, a pro-metastatic transcription factor, functionally interacts with the Androgen Receptor (AR) to regulate PIP expression. Runx2 expression in C4-2B cells synergized with AR to promote PIP expression, whereas its knockdown in T47D BCa cells abrogated basal as well as hormone stimulated PIP expression. Chromatin immunoprecipitation (ChIP) assays showed that Runx2 and AR co-occupied an enhancer element located ~11kb upstream of the PIP open reading frame, and that Runx2 facilitated AR recruitment to the enhancer. PIP knockdown in T47D cells compromised DHT-stimulated expression of multiple AR target genes including PSA, FKBP5, FASN, and SGK1. The inhibition of AR activity due to loss of PIP was attributable at least in part to abrogation of its nuclear translocation. PIP knockdown also suppressed T47D cell proliferation driven by either serum growth factors or dihydrotestosterone (DHT). Our data suggest that Runx2 controls a positive feedback loop between androgen signaling and PIP, and pharmacological inhibition of PIP may be useful to treat PIP positive tumors. PMID:21809344

Baniwal, Sanjeev K; Little, Gillian H; Chimge, Nyam-Osor; Frenkel, Baruch

2012-01-01

29

The Role of Prolactin Receptor in GH Signaling in Breast Cancer Cells  

PubMed Central

GH and prolactin (PRL) are structurally related hormones that exert important effects in disparate target tissues. Their receptors (GHR and PRLR) reside in the cytokine receptor superfamily and share signaling pathways. In humans, GH binds both GHR and PRLR, whereas PRL binds only PRLR. Both hormones and their receptors may be relevant in certain human and rodent cancers, including breast cancer. GH and PRL promote signaling in human T47D breast cancer cells that express both GHR and PRLR. Furthermore, GHR and PRLR associate in a fashion augmented acutely by GH, even though GH primarily activates PRLR, rather than GHR, in these cells. To better understand PRLR's impact, we examined the effects of PRLR knockdown on GHR availability and GH sensitivity in T47D cells. T47D-ShPRLR cells, in which PRLR expression was reduced by stable short hairpin RNA (shRNA) expression, were compared with T47D-SCR control cells. PRLR knockdown decreased the rate of GHR proteolytic turnover, yielding GHR protein increase and ensuing sensitization of these cells to GHR signaling events including phosphorylation of GHR, Janus kinase 2, and signal transducer and activator of transcription 5 (STAT5). Unlike in T47D-SCR cells, acute GH signaling in T47D-ShPRLR cells was not blocked by the PRLR antagonist G129R but was inhibited by the GHR-specific antagonist, anti-GHRext-mAb. Thus, GH's use of GHR rather than PRLR was manifested when PRLR was reduced. In contrast to acute effects, GH incubation for 2 h or longer yielded diminished STAT5 phosphorylation in T47D-ShPRLR cells compared with T47D-SCR, a finding perhaps explained by markedly greater GH-induced GHR down-regulation in cells with diminished PRLR. However, when stimulated with repeated 1-h pulses of GH separated by 3-h washout periods to more faithfully mimic physiological GH pulsatility, T47D-ShPRLR cells exhibited greater transactivation of a STAT5-responsive luciferase reporter than did T47D-SCR cells. Our data suggest that PRLR's presence meaningfully affects GHR use in breast cancer cells. PMID:23192981

Xu, Jie; Sun, Dongmei; Jiang, Jing; Deng, Luqin; Zhang, Yue; Yu, Hao; Bahl, Deepti; Langenheim, John F.; Chen, Wen Y.; Fuchs, Serge Y.

2013-01-01

30

Concentration-dependent mitogenic and antiproliferative actions of 2-methoxyestradiol in estrogen receptor-positive human breast cancer cells  

Microsoft Academic Search

We compared in this study the effects of 2-methoxyestradiol (2-MeO-E2) on the growth of two estrogen receptor (ER)-negative human breast cancer cell lines (MDA-MB-231 and MDA-MB-435s) and two ER-positive human breast cancer cell lines (MCF-7 and T-47D). 2-MeO-E2 exerted a concentration-dependent antiproliferative action in the ER-negative MDA-MB-231 and MDA-MB-435s cells. The presence or absence of exogenous 17?-estradiol (E2) in the

Zhi-Jian Liu; Bao Ting Zhu

2004-01-01

31

Isomers Geometric dan efek sitotoksik pada sel T47D dari analog kurkumin PGV-0 and PGV-1* Geometric Isomers and Cytotoxic Effect On T47D Cells of Curcumin Analogues PGV-0 and PGV-1  

Microsoft Academic Search

Analog kurkumin 2,5-bis-(4'-hidroksi-3'-metoksi)-benzilidinsiklopen- tanon atau PGV-0 dan 2,5-bis-(4'-hidroksi-3',5'-dimetil)-benzilidinsiklo- pentanon atau PGV-1 memiliki potensi untuk dikembangkan sebagai senyawa yang bersifat sitotoksik. Penelitian ini dilakukan untuk menentukan struktur geometrik kedua senyawa tersebut dan efek sitotoksiknya terhadap sel kanker payudara T47D. Senyawa dielusidasi dengan LC-MS, 1H-NMR dan 13C-NMR, HMBC, HMQC dan NOESY untuk menentukan struktur geometriknya. Senyawa diuji efeksitotoksiknya terhadap sel T47D dengan

Muhammad Da' i

32

EFFECTS OF BENZO[A]PYRENE AND ARSENITE ON CYP1A1 AND CYP1B1 MRNA LEVELS IN T-47D HUMAN BREAST CANCER CELLS: DETERMINATION BY A BRANCHED DNA ASSAY. (R827180)  

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

33

INDUCTION OF CYP1A1 AND CYP1B1 IN T-47D HUMAN BREAST CANCER CELLS BY BENZO[A]PYRENE IS DIMINISHED BY ARSENITE. (R827180)  

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

34

Undecylprodigiosin selectively induces apoptosis in human breast carcinoma cells independent of p53  

SciTech Connect

Undecylprodigiosin (UP) is a bacterial bioactive metabolite produced by Streptomyces and Serratia. In this study, we explored the anticancer effect of UP. Human breast carcinoma cell lines BT-20, MCF-7, MDA-MB-231 and T47D and one nonmalignant human breast epithelial cell line, MCF-10A, were tested in this study. We found that UP exerted a potent cytotoxicity against all breast carcinoma cell lines in a dose- and time-dependent manner. In contrast, UP showed limited toxicity to MCF-10A cells, indicating UP's cytotoxic effect is selective for malignant cells. UP's cytotoxic effect was due to apoptosis, as confirmed by positive TUNEL signals, annexin V-binding, caspase 9 activation and PARP cleavage. Notably, UP-induced apoptosis was blocked by the pan-caspase inhibitor z-VAD.fmk, further indicating the involvement of caspase activity. Moreover, UP caused a marked decrease of the levels of antiapoptotic BCL-X{sub L}, Survivin and XIAP while enhancing the levels of proapoptotic BIK, BIM, MCL-1S and NOXA, consequently favoring induction of apoptosis. Additionally, we found that cells with functional p53 (MCF-7, T47D) or mutant p53 (BT-20, MDA-MB-231) were both susceptible to UP's cytotoxicity. Importantly, UP was able to induce apoptosis in MCF-7 cells with p53 knockdown by RNA interference, confirming the dispensability of p53 in UP-induced apoptosis. Overall, our results establish that UP induces p53-independent apoptosis in breast carcinoma cells with no marked toxicity to nonmalignant cells, raising the possibility of its use as a new chemotherapeutic drug for breast cancer irrespective of p53 status.

Ho, T.-F. [Institute of Biomedical Sciences, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung 40227, Taiwan (China); Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan (China); Department of Medical Technology, Central Taiwan University of Science and Technology, Taichung 40605, Taiwan (China); Ma, C.-J. [Institute of Biomedical Sciences, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung 40227, Taiwan (China); Lu, C.-H. [Institute of Biomedical Sciences, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung 40227, Taiwan (China); Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Tsai, Yo-Ting [Institute of Biomedical Sciences, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung 40227, Taiwan (China); Wei, Y.-H. [Graduate School of Biotechnology and Bioinformatics, Yuan Ze University, Taoyuan, Taiwan (China); Chang, J.-S. [Department of Chemical Engineering, National Cheng Kung University, Tainan, Taiwan (China); Lai, J.-K. [Institute of Biomedical Sciences, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung 40227, Taiwan (China); Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan (China); Cheuh, Pin-Ju [Institute of Biomedical Sciences, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung 40227, Taiwan (China); Yeh, C.-T. [Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan (China); Tang, P.-C. [Department of Animal Science, National Chung Hsing University, Taichung, Taiwan (China); Jingua, T.C.; Ko, J.-L. [Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan (China); Liu, F.-S. [Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Yen, H.E. [Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan (China)] (and others)

2007-12-15

35

B-cell lymphoma 6 protein stimulates oncogenicity of human breast cancer cells  

PubMed Central

Background B-cell lymphoma 6 (BCL6) protein, an evolutionarily conserved zinc finger transcription factor, showed to be highly expressed in various human cancers in addition to malignancies in the lymphoid system. This study investigated the role of BCL6 expression in breast cancer and its clinical significance in breast cancer patients. Methods Expression of BCL6 protein was assessed using in situ hybridization and immunohistochemistry in 127 breast cancer patients and 50 patients with breast benign disease as well as in breast cell lines. Expression of BCL6 was restored or knocked down in two breast cancer cell lines (MCF-7 and T47D) using BCL6 cDNA and siRNA, respectively. The phenotypic change of these breast cancer cell lines was assessed using cell viability MTT, Transwell invasion, colony formation, and flow cytometry assays and in a xenograft mice model. Luciferase reporter gene, immunoblot, and qRT-PCR were used to investigate the molecular events after manipulated BCL6 expression in breast cancer cells. Results BCL6 protein was highly expressed in breast cancer cell lines and tissue specimens and expression of BCL6 protein was associated with disease progression and poor survival of breast cancer patients. In vitro, the forced expression of BCL6 results in increased proliferation, anchorage-independent growth, migration, invasion and survival of breast cancer cell lines, whereas knockdown of BCL6 expression reduced these oncogenic properties of breast cancer cells. Moreover, forced expression of BCL6 increased tumor growth and invasiveness in a nude mouse xenograft model. At the gene level, BCL6 was a target gene of miR-339-5p. Expression of BCL6 induced expression of CXCR4 and cyclinD1 proteins. Conclusions The current study demonstrated the oncogenic property of BCL6 in breast cancer and further study could target BCL6 as a novel potential therapeutic strategy for breast cancer. PMID:24917186

2014-01-01

36

A survey of human breast cancer sensitivity to growth inhibition by calmodulin antagonists in tissue culture.  

PubMed

We compared the ability of N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide (W-13), a calmodulin antagonist, to inhibit the growth of seven human breast cancer cell lines in tissue culture, to determine whether drug sensitivity was related to estrogen receptor (ER) status, tamoxifen resistance (tamr), or levels of calmodulin activity. We examined three ER+ (estrogen receptor-positive) cell lines (MCF-7, ZR-75-1B, and T47D), two ER+/tamr lines (LY2 and RR), and two ER- (estrogen receptor-negative) cell lines (MDA-MB-231 and MDA-MB-435). There was no difference in the inhibition of cell growth by W-13 in MCF-7 cells and the two tamr MCF-7 cell derivatives, LY2 and RR. In addition, the sensitivity to W-13 did not appear to be related to ER status. Although the mean Ki of the five ER+ cell lines (31 microM) was somewhat higher than the mean Ki of the two ER- cell lines (23 microM), the two cell lines most sensitive to W-13 were the ER+ T47D cells (Ki 15 microM) and the ER- MDA-MB-435 cells (Ki 10 microM). Calmodulin activity was measured in three representative cell lines, MCF-7, LY2, and MDA-MB-435. Calmodulin levels were higher in the most sensitive cell line (MDA-MB-435, 2.7 ng calmodulin/micrograms protein) than in the two less sensitive cell lines, MCF-7 and LY2 (1.3 and 1.6 ng calmodulin/micrograms protein, respectively). However, the MCF-7, LY2, and MDA-MB-435 cells were equally sensitive to another specific calmodulin antagonist, calmidazolium. We conclude that neither ER status, tamoxifen resistance, nor levels of calmodulin activity predict the sensitivity of human breast cancer cell lines to growth inhibition in tissue culture by calmodulin antagonists. PMID:8031308

Strobl, J S; Peterson, V A; Woodfork, K A

1994-06-15

37

The Novel C24D Synthetic Polypeptide Inhibits Binding of Placenta Immunosuppressive Ferritin to Human T Cells and Elicits Anti–Breast Cancer Immunity In Vitro and In Vivo1  

PubMed Central

Immune tolerance mechanisms supporting normal human pregnancy are exploited by breast cancer and other malignancies. We cloned from human placenta and breast cancer cells the novel human immunomodulator named placenta immunosuppressive ferritin (PLIF). PLIF is composed of a ferritin heavy chain–like domain and a novel cytokine-like domain, named C48. Both intact PLIF and C48 inhibit T cell proliferation. Blocking PLIF by specific antibodies in a tolerant breast cancer model in nude mice resulted in tumor cell apoptosis and rejection. This prompted us to study active immune preventive strategies targeting PLIF activity. Currently, we report on the design and synthesis of the novel C24D polypeptide, which inhibits the binding of PLIF to T cells and therefore inhibits the immune suppressive effect of PLIF. The effect of C24D on the generation of anti–breast cancer cytotoxic T lymphocytes (CTLs) was studied in vitro in cultures of MCF-7 (HLA-A2+) or T47D (HLA-A2?) breast cancer cells incubated with peripheral blood mononuclear cells (PBMCs) from healthy blood donors. We found that C24D treatment exclusively induced development of CTLs. On reactivation by their specific target cells, the CTLs secreted interferon-? and induced target apoptosis. Anti–MCF-7 CTLs were cross-cytotoxic to MDA-MB-231 (HLA-A2+) triple-negative breast cancer but not to T47D. Moreover, C24D treatment in vivo inhibited the growth of MCF-7 tumors engrafted in immune-compromised nude mice transfused with naïve allogeneic human PBMCs. Our results demonstrate that C24D treatment breakdown breast cancer induced tolerance enabling the initiation of effective anti-tumor immune response. PMID:25246274

Solodeev, Inna; Zahalka, Muayad A.; Moroz, Chaya

2014-01-01

38

Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer  

PubMed Central

Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. PMID:22841774

Yu, Wei; Chai, Hongyan; Li, Ying; Zhao, Haixia; Xie, Xianfei; Zheng, Hao; Wang, Chenlong; Wang, Xue; Yang, Guifang; Cai, Xiaojun; Falck, John R.; Yang, Jing

2012-01-01

39

Aluminium and human breast diseases  

Microsoft Academic Search

The human breast is exposed to aluminium from many sources including diet and personal care products, but dermal application of aluminium-based antiperspirant salts provides a local long-term source of exposure. Recent measurements have shown that aluminium is present in both tissue and fat of the human breast but at levels which vary both between breasts and between tissue samples from

P. D. Darbre; D. Pugazhendhi; F. Mannello

40

Characterization of a Novel and Functional Human Prolactin Receptor Isoform (DeltaS1PRLr) Containing Only One Extracellular Fibronectin-Like Domain  

Microsoft Academic Search

Prolactin (PRL)-dependent signaling occurs as the result of ligand-induced homodimerization of the PRL receptor (PRLr). To date, short, intermediate, and long human PRLr isoforms have been charac- terized. To investigate the expression of other possible human PRLr isoforms, RT-PCR was per- formed on mRNA isolated from the breast carci- noma cell line T47D. A 1.5-kb PCR fragment was isolated, subcloned,

J. BRADFORD KLINE; MICHAEL A. RYCYZYN; CHARLES V. CLEVENGER

2002-01-01

41

Development of the Human Breast  

PubMed Central

Mammalia are so named based on the presence of the mammary gland in the breast. The mammary gland is an epidermal appendage, derived from the apocrine glands. The human breast consists of the parenchyma and stroma, originating from ectodermal and mesodermal elements, respectively. Development of the human breast is distinctive for several reasons. The human breast houses the mammary gland that produces and delivers milk through development of an extensive tree-like network of branched ducts. It is also characterized by cellular plasticity, with extensive remodeling in adulthood, a factor that increases its susceptibility to carcinogenesis. Also, breast development occurs in distinct stages via complex epithelial–mesenchymal interactions, orchestrated by signaling pathways under the regulation of systemic hormones. Congenital and acquired disorders of the breast often have a basis in development, making its study essential to understanding breast pathology. PMID:24872732

Javed, Asma; Lteif, Aida

2013-01-01

42

Comparative Chemosensitivity Profiles in Three Human Breast Cancer Cell Lines with the ATP-Cell Viability Assay  

Microsoft Academic Search

In this study the dose-response curves for doxorubicin, pirarubicin, 5-fluoro-uracil, 4-hydroperoxy-cyclophosphamide and taxol were obtained in three breast cancer cell lines (MCF-7, T47D and BT-20). The ATP cell viability assay was chosen to evaluate the chemosensitivity profiles and was a reproducible, practicable method to assess drug response in breast cancer cell lines. The IC50 values were calculated on the median

Ossi R. Koechli; Bernd-Uwe Sevin; James P. Perras; Roberto Angioli; Michael Untch; Albert Steren; Cheppail Ramachandran; Hervy E. Averette

1994-01-01

43

Comparative chemosensitivity profiles in three human breast cancer cell lines with the ATP-cell viability assay.  

PubMed

In this study the dose-response curves for doxorubicin, pirarubicin, 5-fluorouracil, 4-hydroperoxy-cyclophosphamide and taxol were obtained in three breast cancer cell lines (MCF-7, T47D and BT-20). The ATP cell viability assay was chosen to evaluate the chemosensitivity profiles and was a reproducible, practicable method to assess drug response in breast cancer cell lines. The IC50 values were calculated on the median effect principle and indicated that taxol was the most active drug tested in this study with a mean IC50 value of 0.02 microM. This in vitro effect correlated well with clinical observations in metastatic breast cancer where taxol proved to be a vary active drug. Pirarubicin was the second most active drug tested with an IC50 value 10 times less compared to that of doxorubicin. The results obtained with the ATP cell viability assay are promising, therefore further testing with drug combination chemotherapy and fresh human breast cancer tumor testing are warranted and ongoing. PMID:7970502

Koechli, O R; Sevin, B U; Perras, J P; Angioli, R; Untch, M; Steren, A; Ramachandran, C; Averette, H E

1994-01-01

44

RIP3 overexpression sensitizes human breast cancer cells to parthenolide in vitro via intracellular ROS accumulation  

PubMed Central

Aim: Receptor-interacting protein 3 (RIP3) is involved in tumor necrosis factor receptor signaling, and results in NF-?B-mediated prosurvival signaling and programmed cell death. The aim of this study was to determine whether overexpression of the RIP3 gene could sensitize human breast cancer cells to parthenolide in vitro. Methods: The expression of RIP3 mRNA in human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-435 and T47D) was detected using RT-PCR. Both MDA-MB-231 and MCF-7 cells were transfected with RIP3 expression or blank vectors via lentivirus. Cell viability was measured with MTT assay; intracellular ROS level and cell apoptosis were analyzed using flow cytometry. Results: RIP3 mRNA expression was not detected in the four human breast cancer cell lines tested. However, the transfection induced higher levels of RIP3 protein in MCF-7 and MDA-MB-231 cells. Furthermore, overexpression of RIP3 decreased the IC50 values of parthenolide from 17.6 to 12.6 ?mol/L in MCF-7 cells, and from 16.6 to 9.9 ?mol/L in MDA-MB-231 cells. Moreover, overexpression of RIP3 significantly increased parthenolide-induced apoptosis and ROS accumulation in MCF-7 and MDA-MB-231 cells. Pretreatment with N-acetyl-cysteine abrogated the increased sensitivity of RIP3-transfected MCF-7 and MDA-MB-231 cells to parthenolide. Conclusion: Overexpression of RIP3 sensitizes MCF-7 and MDA-MB-231 breast cancer cells to parthenolide in vitro via intracellular ROS accumulation. PMID:24909514

Lu, Can; Zhou, Li-yan; Xu, Hui-jun; Chen, Xing-yu; Tong, Zhong-sheng; Liu, Xiao-dong; Jia, Yong-sheng; Chen, Yue

2014-01-01

45

Synthesis of new N,N'-bis[1-aryl-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides and evaluation of their cytotoxicity against human hepatoma and breast cancer cells.  

PubMed

N,N'-Bis[1-aryl-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides were synthesized by the reaction of 2 mols of 1-aryl-3-(piperidine-1-yl)-1-propanone hydrochlorides with 1?mol of hydrazine hydrate. Aryl part was C?H? (P1), 4-CH?C?H? (P2), 4-CH?OC?H? (P3), 4-HOC?H? (P4), 4-ClC?H? (P5), 3-CH?OC?H? (P6), 4-FC?H? (P7) and 4-BrC?H? (P8). Except P1, all compounds were reported for the first time. The chemical structures were confirmed by UV, (1)H NMR, (13)C NMR and HRMS spectra. P1, P2, P7 and P8 against human hepatoma (Huh7) cells and P1, P2, P4, P5, P6, P7 and P8 against breast cancer (T47D) cells have shown cytotoxicity. P1, P2 and P7 had more potent cytotoxicity against Huh7 cells than the reference compound 5-FU, whereas only P2 was more potent than the 5-FU against T47D cells. Representative compound P7 inhibited the mitochondrial respiration at 144, 264 and 424?µM concentrations dose-dependantly in liver homogenates. The results suggest that P1, P2, P7 and P8 may serve as model compounds for further synthetic studies. PMID:23859151

Kucukoglu, Kaan; Gul, H Inci; Cetin-Atalay, Rengul; Baratli, Yosra; Charles, Anne-Laure; Sukuroglu, Murat; Gul, Mustafa; Geny, Bernard

2014-06-01

46

KISS1R induces invasiveness of estrogen receptor-negative human mammary epithelial and breast cancer cells.  

PubMed

Kisspeptins (KPs), peptide products of the KISS1 metastasis-suppressor gene, are endogenous ligands for a G protein-coupled receptor (KISS1R). KISS1 acts as a metastasis suppressor in numerous human cancers. However, recent studies have demonstrated that an increase in KISS1 and KISS1R expression in patient breast tumors correlates with higher tumor grade and metastatic potential. We have shown that KP-10 stimulates invasion of estrogen receptor ? (ER?)-negative MDA-MB-231 breast cancer cells via transactivation of the epidermal growth factor receptor (EGFR). Here, we report that either KP-10 treatment of ER?-negative nonmalignant mammary epithelial MCF10A cells or expression of KISS1R in MCF10A cells induced a mesenchymal phenotype and stimulated invasiveness. Similarly, exogenous expression of KISS1R in ER?-negative SKBR3 breast cancer cells was sufficient to trigger invasion and induced extravasation in vivo. In contrast, KP-10 failed to transactivate EGFR or stimulate invasiveness in the ER?-positive MCF7 and T47D breast cancer cells. This suggested that ER? negatively regulates KISS1R-dependent breast cancer cell migration, invasion, and EGFR transactivation. In support of this, we found that these KP-10-induced effects were ablated upon exogenous expression of ER? in the MDA-MB-231 cells, by down-regulating KISS1R expression. Lastly, we have identified IQGAP1, an actin cytoskeletal binding protein as a novel binding partner of KISS1R, and have shown that KISS1R regulates EGFR transactivation in breast cancer cells in an IQGAP1-dependent manner. Overall, our data strongly suggest that the ER? status of mammary cells dictates whether KISS1R may be a novel clinical target for treating breast cancer metastasis. PMID:23525242

Cvetkovic, Donna; Dragan, Magdalena; Leith, Sean J; Mir, Zuhaib M; Leong, Hon S; Pampillo, Macarena; Lewis, John D; Babwah, Andy V; Bhattacharya, Moshmi

2013-06-01

47

Boswellia sacra essential oil induces tumor cell-specific apoptosis and suppresses tumor aggressiveness in cultured human breast cancer cells  

PubMed Central

Background Gum resins obtained from trees of the Burseraceae family (Boswellia sp.) are important ingredients in incense and perfumes. Extracts prepared from Boswellia sp. gum resins have been shown to possess anti-inflammatory and anti-neoplastic effects. Essential oil prepared by distillation of the gum resin traditionally used for aromatic therapy has also been shown to have tumor cell-specific anti-proliferative and pro-apoptotic activities. The objective of this study was to optimize conditions for preparing Boswellea sacra essential oil with the highest biological activity in inducing tumor cell-specific cytotoxicity and suppressing aggressive tumor phenotypes in human breast cancer cells. Methods Boswellia sacra essential oil was prepared from Omani Hougari grade resins through hydrodistillation at 78 or 100 oC for 12 hours. Chemical compositions were identified by gas chromatography-mass spectrometry; and total boswellic acids contents were quantified by high-performance liquid chromatography. Boswellia sacra essential oil-mediated cell viability and death were studied in established human breast cancer cell lines (T47D, MCF7, MDA-MB-231) and an immortalized normal human breast cell line (MCF10-2A). Apoptosis was assayed by genomic DNA fragmentation. Anti-invasive and anti-multicellular tumor properties were evaluated by cellular network and spheroid formation models, respectively. Western blot analysis was performed to study Boswellia sacra essential oil-regulated proteins involved in apoptosis, signaling pathways, and cell cycle regulation. Results More abundant high molecular weight compounds, including boswellic acids, were present in Boswellia sacra essential oil prepared at 100 oC hydrodistillation. All three human breast cancer cell lines were sensitive to essential oil treatment with reduced cell viability and elevated cell death, whereas the immortalized normal human breast cell line was more resistant to essential oil treatment. Boswellia sacra essential oil hydrodistilled at 100 oC was more potent than the essential oil prepared at 78 oC in inducing cancer cell death, preventing the cellular network formation (MDA-MB-231) cells on Matrigel, causing the breakdown of multicellular tumor spheroids (T47D cells), and regulating molecules involved in apoptosis, signal transduction, and cell cycle progression. Conclusions Similar to our previous observations in human bladder cancer cells, Boswellia sacra essential oil induces breast cancer cell-specific cytotoxicity. Suppression of cellular network formation and disruption of spheroid development of breast cancer cells by Boswellia sacra essential oil suggest that the essential oil may be effective for advanced breast cancer. Consistently, the essential oil represses signaling pathways and cell cycle regulators that have been proposed as therapeutic targets for breast cancer. Future pre-clinical and clinical studies are urgently needed to evaluate the safety and efficacy of Boswellia sacra essential oil as a therapeutic agent for treating breast cancer. PMID:22171782

2011-01-01

48

Prodigiosin down-regulates survivin to facilitate paclitaxel sensitization in human breast carcinoma cell lines  

SciTech Connect

Prodigiosin is a bacterial metabolite with potent anticancer activity, which is attributed to its proapoptotic effect selectively active in malignant cells. Still, the molecular mechanisms whereby prodigiosin induces apoptosis remain largely unknown. In particular, the role of survivin, a vital inhibitor of apoptosis, in prodigiosin-induced apoptosis has never been addressed before and hence was the primary goal of this study. Our results showed that prodigiosin dose-dependently induced down-regulation of survivin in multiple breast carcinoma cell lines, including MCF-7, T-47D and MDA-MB-231. This down-regulation is mainly regulated at the level of transcription, as prodigiosin reduced the levels of both survivin mRNA and survivin promoter activity but failed to rescue survivin expression when proteasome-mediated degradation is abolished. Importantly, overexpression of survivin rendered cells more resistant to prodigiosin, indicating an essential role of survivin down-regulation in prodigiosin-induced apoptosis. In addition, we found that prodigiosin synergistically enhanced cell death induced by paclitaxel, a chemotherapy drug known to up-regulate survivin that in turn confers its own resistance. This paclitaxel sensitization effect of prodigiosin is ascribed to the lowering of survivin expression, because prodigiosin was shown to counteract survivin induction by paclitaxel and, notably, the sensitization effect was severely abrogated in cells that overexpress survivin. Taken together, our results argue that down-regulation of survivin is an integral component mediating prodigiosin-induced apoptosis in human breast cancer cells, and further suggest the potential of prodigiosin to sensitize anticancer drugs, including paclitaxel, in the treatment of breast cancer.

Ho, T.-F. [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Department of Medical Technology, Central Taiwan University of Science and Technology, Taichung, Taiwan (China); Peng, Y.-T.; Chuang, S.-M.; Lin, S.-C.; Feng, B.-L. [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Lu, C.-H. [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Yu, W.-J. [Department of Chemical Engineering, National Cheng Kung University, Tainan, Taiwan (China); Chang, J.-S. [Department of Chemical Engineering, National Cheng Kung University, Tainan, Taiwan (China); Sustainable Environment Research Center, National Cheng Kung University, Tainan, Taiwan (China)], E-mail: changjs@mail.ncku.edu.tw; Chang, C.-C. [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China)], E-mail: chia_che@dragon.nchu.edu.tw

2009-03-01

49

Transforming growth factors type beta 1 and beta 2 are equipotent growth inhibitors of human breast cancer cell lines.  

PubMed

At least one member of the TGF-beta family, TGF-beta 1, has been previously shown to inhibit the anchorage-independent growth of some human breast cancer cell lines (Knabbe et al., 1987; Arteaga et al., 1988). Members of the TGF-beta family might, therefore, provide new strategies for breast cancer therapy. We have studied the inhibitory effects of TGF-beta 1 and TGF-beta 2 on the anchorage-independent growth of the oestrogen receptor-negative cell lines MDA-MB-231, SK-BR-3, Hs578T, MDA-MB-468, and MDA-MB-468-S4 (an MDA-MB-468 clone not growth inhibited by EGF) and the estrogen receptor-positive cell lines MCF7, ZR-75-1, T-47D. TGF-beta 1 and TGF-beta 2 caused a 75-90% growth inhibition of MDA-MB-231, SK-BR-3, Hs578T, and MDA-MB-468 cells and a 50% growth inhibition of ZR-75-1 and early passage (less than 100) MCF7 cells. T-47D cells responded to TGF-beta only in serum-free conditions in the presence of IGF-1 or EGF. The growth of MDA-MB-468-S4 cells and late passage (greater than 500) MCF7 cells was not inhibited by TGF-beta 1 or TGF-beta 2. TGF-beta-sensitive MCF7 and MDA-MB-231 cells did not respond to Muellerian inhibiting substance (MIS), a TGF-beta-related polypeptide. TGF-beta 1 or TGF-beta 2 were mutually competitive for receptor binding with a similar affinity (Kd 25-130 pM, 1,000-13,000 sites per cell). To determine the time course of the TGF-beta effect, an anchorage-dependent growth assay was carried out using MDA-MB-231 cells. Growth inhibition occurred at 6 days, and cell-cycle changes were seen 12 hr after the addition of TGF-beta. Cells accumulated in the G1 phase and were thus inhibited from entering the S-phase. These data indicate that TGF-beta is a potent growth inhibitor in most breast cancer cell lines and provide a basis for studying TGF-beta effects in vivo. PMID:2808542

Zugmaier, G; Ennis, B W; Deschauer, B; Katz, D; Knabbe, C; Wilding, G; Daly, P; Lippman, M E; Dickson, R B

1989-11-01

50

Caprin-1 is a novel microRNA-223 target for regulating the proliferation and invasion of human breast cancer cells.  

PubMed

MicroRNAs (miRNAs) are 21-22 nucleotides regulatory small non-coding RNAs that inhibit gene expression by binding to complementary sequences especially the 3' untranslated region (3'UTR) of mRNA. One miRNA can target many messenger RNAs, leading to a complex metabolic network. Previous studies have shown that miRNA-223 regulates migration and invasion of tumor cells and targets cytoplasmic activation/proliferation-associated protein-1 (Caprin-1). In the present study, we detected the expression of miRNA-223 and Caprin-1 in MCF-7, T-47D and MDA-MB-231 cancer cell lines, and MCF-10A normal breast cell line, and analyzed the role of miRNA-223 in Caprin-1-induced proliferation and invasion of human breast cancer cells. We found that miRNA-223 expression levels are significantly lower in MCF-7, T-47D and MDA-MB-231 cancer cells than in MCF-10A normal breast cells, while Caprin-1 expression is higher in cancer cells than in normal breast cells. The most malignant cancer cell line MDA-MB-231 has the lowest expression of miR-223, but the highest expression of Caprin-1. Further, we found that miR-223 targets the 3'UTR of Caprin-1 miRNA and down-regulates the expression of Caprin-1. We also found that over-expression of Caprin-1 can promote the proliferation and the invasion of breast cancer cells, but miRNA-223 can inhibit the proliferation and the invasion. miRNA-223-induced inhibition can be reversed by ectopic over-expression of Caprin-1. These findings suggest that miR-223 may suppress the proliferation and invasion of cancer cells by directly targeting Caprin-1. Our study also indicates that expression levels of miR-223 and Caprin-1 can be used to predict the state of cancer in breast cancer patient. PMID:23953883

Gong, Bo; Hu, Heyu; Chen, Jia; Cao, Shuang; Yu, Jing; Xue, Jianxiang; Chen, Fuhua; Cai, Ye; He, Hong; Zhang, Lei

2013-09-01

51

Immunotherapeutic Potential of Anti-Human Endogenous Retrovirus-K Envelope Protein Antibodies in Targeting Breast Tumors  

PubMed Central

Background The envelope (env) protein of the human endogenous retrovirus type K (HERV-K) family is commonly expressed on the surface of breast cancer cells. We assessed whether HERV-K env is a potential target for antibody-based immunotherapy of breast cancer. Methods We examined the expression of HERV-K env protein in various malignant (MDA-MB-231, MCF-7, SKBR3, MDA-MB-453, T47D, and ZR-75-1) and nonmalignant (MCF-10A and MCF-10AT) human breast cell lines by immunoblot, enzyme-linked immunosorbent assay, immunofluorescence staining, and flow cytometry. Anti-HERV-K env monoclonal antibodies (mAbs; 6H5, 4D1, 4E11, 6E11, and 4E6) were used to target expression of HERV-K, and antitumor effects were assessed by quantifying growth and apoptosis of breast cancer cells in vitro, and tumor growth in vivo in mice (n = 5 per group) bearing xenograft tumors. The mechanisms responsible for 6H5 mAb–mediated effects were investigated by microarray assays, flow cytometry, immunoblot, and immunofluorescence staining. The expression of HERV-K env protein was assessed in primary breast tumors (n = 223) by immunohistochemistry. All statistical tests were two-sided. Results The expression of HERV-K env protein in malignant breast cancer cell lines was substantially higher than nonmalignant breast cells. Anti–HERV-K-specific mAbs inhibited growth and induced apoptosis of breast cancer cells in vitro. Mice treated with 6H5 mAb showed statistically significantly reduced growth of xenograft tumors compared with mice treated with control immunoglobulin (control [mIgG] vs 6H5 mAb, for tumors originating from MDA-MB-231 cells, mean size = 1448.33 vs 475.44 mm3; difference = 972.89 mm3, 95% CI = 470.17 to 1475.61 mm3; P < .001). Several proteins involved in the apoptotic signaling pathways were overexpressed in vitro in 6H5 mAb–treated malignant breast cells compared with mIgG-treated control. HERV-K expression was detected in 148 (66%) of 223 primary breast tumors, and a higher rate of lymph node metastasis was associated with HERV-K-positive compared with HERV-K-negative tumors (43% vs 23%, P = .003). Conclusion Monoclonal antibodies against HERV-K env protein show potential as novel immunotherapeutic agents for breast cancer therapy. PMID:22247020

Rycaj, Kiera; Plummer, Joshua B.; Li, Ming; Yin, Bingnan; Frerich, Katherine; Garza, Jeremy G.; Shen, Jianjun; Lin, Kevin; Yan, Peisha; Glynn, Sharon A.; Dorsey, Tiffany H.; Hunt, Kelly K.; Ambs, Stefan; Johanning, Gary L.

2012-01-01

52

Cloning and characterization of a 77-kDa oestrogen receptor isolated from a human breast cancer cell line.  

PubMed Central

We have cloned and characterized a 77-kDa oestrogen receptor (ER) from an oestrogen-independent subclone of the MCF-7 human breast cancer cell line. This receptor contains an in-frame, tandem duplication of exons 6 and 7, located in the steroid-binding domain of the ER. This mutation has abrogated ligand binding, but not DNA binding, in this mutant ER. We previously described the partial structure of a unique oestrogen receptor (ER) that is expressed in an oestrogen-independent MCF-7:2A subclone of the breast cancer cell line MCF-7 (Pink JJ, Wu SQ, Wolf DM, Bilimoria MM, Jordan VC 1996a, Nucleic Acids Res 24 962-969). Sequence analyses determined the molecular weight of this 80-kDa ER to be 77 kDa, and hereafter this protein will be designated as ER77. Examination of the entire coding sequence of the ER77 mRNA indicates that it contains a tandem duplication of exons 6 and 7. Using a coupled transcription/translation system, a 77-kDa ER, which corresponds to the protein observed in the MCF-7:2A cells, was expressed. The ER77 protein does not bind the ligands [3H] oestradiol or [3H]tamoxifen aziridine. In DNA binding gel shift assays, the in vitro synthesized ER77 binds to a consensus vitellogenin A2 oestrogen-response element. In transient transfection experiments, the mutant ER, alone or in combination with the wild-type ER, does not induce expression of an oestrogen-responsive luciferase reporter construct. In fact, expression of the ER77 in the ER-positive T47D:A18 cell line inhibits E2-induced luciferase expression. Overexpression of wild-type ER in T47D:A18 cells leads to elevated constitutive expression of the luciferase reporter, which was inhibited by co-transfection with ER77. These data suggest that the ER77 can interfere with normal ER activity and does not act as a constitutive activator of oestrogen-independent growth in MCF-7:2A cells. Consequently, the constitutive growth observed in MCF-7:2A cells is probably the result of other ER-mediated pathways. Images Figure 2 Figure 3 Figure 4 Figure 5 PMID:9000593

Pink, J. J.; Fritsch, M.; Bilimoria, M. M.; Assikis, V. J.; Jordan, V. C.

1997-01-01

53

Early estrogen-induced metabolic changes and their inhibition by actinomycin D and cycloheximide in human breast cancer cells: sup 31 P and sup 13 C NMR studies  

SciTech Connect

Metabolic changes following estrogen stimulation and the inhibition of these changes in the presence of actinomycin D and cycloheximide were monitored continuously in perfused human breast cancer T47D clone 11 cells with {sup 31}P and {sup 13}C NMR techniques. The experiments were performed by estrogen rescue of tamoxifen-treated cells. Immediately after perfusion with estrogen-containing medium, a continuous enhancement in the rates of glucose consumption, lactate production by glycolysis, and glutamate synthesis by the Krebs cycle occurred with a persistent 2-fold increase at 4 hr. Pretreatment with either actinomycin D or cycloheximide, at concentrations known to inhibit mRNA and protein synthesis, respectively, and simultaneous treatment with estrogen and each inhibitor prevented the estrogen-induced changes in glucose metabolism. This suggested that the observed estrogen stimulation required synthesis of mRNA and protein. These inhibitors also modulated several metabolic activities that were not related to estrogen stimulation. The observed changes in the in vivo kinetics of glucose metabolism may provide a means for the early detection of the response of human breast cancer cells to estrogen versus tamoxifen treatment.

Neeman, M.; Degani, H. (Weizmann Institute of Science, Rehovot (Israel))

1989-07-01

54

Early estrogen-induced metabolic changes and their inhibition by actinomycin D and cycloheximide in human breast cancer cells: 31P and 13C NMR studies.  

PubMed Central

Metabolic changes following estrogen stimulation and the inhibition of these changes in the presence of actinomycin D and cycloheximide were monitored continuously in perfused human breast cancer T47D clone 11 cells with 31P and 13C NMR techniques. The experiments were performed by estrogen rescue of tamoxifen-treated cells. Immediately after perfusion with estrogen-containing medium, a continuous enhancement in the rates of glucose consumption, lactate production by glycolysis, and glutamate synthesis by the Krebs cycle occurred with a persistent 2-fold increase at 4 hr. The content of phosphocholine had increased by 10% to 30% within the first hour of estrogen stimulation, but the content of the other observed phosphate metabolites as well as the pH remained unchanged. Pretreatment with either actinomycin D or cycloheximide, at concentrations known to inhibit mRNA and protein synthesis, respectively, and simultaneous treatment with estrogen and each inhibitor prevented the estrogen-induced changes in glucose metabolism. This suggested that the observed estrogen stimulation required synthesis of mRNA and protein. These inhibitors also modulated several metabolic activities that were not related to estrogen stimulation. The observed changes in the in vivo kinetics of glucose metabolism may provide a means for the early detection of the response of human breast cancer cells to estrogen versus tamoxifen treatment. PMID:2748604

Neeman, M; Degani, H

1989-01-01

55

[CANCER RESEARCH 63, 71587166, November 1, 2003] The Gene Expression Response of Breast Cancer to Growth Regulators: Patterns  

E-print Network

[CANCER RESEARCH 63, 7158­7166, November 1, 2003] The Gene Expression Response of Breast Cancer transcriptional effects elicited in MCF7, T-47D, and MDA-MB-436 breast cancer cell lines by nine regulators at the gene expression level of diverse regulators of breast cancer growth and links the behavior of breast

Ringnér, Markus

56

The nucleoside antagonist cordycepin causes DNA double strand breaks in breast cancer cells.  

PubMed

The fungal drug cordycepin (3-deoxyadenosine) is known to exert anti-tumor activities, preferentially by interfering with RNA synthesis. We have investigated the effect of cordycepin on human breast epithelial cell lines, ranging from non-malignant MCF10A cells to highly de-differentiated MDA-MB-435 cancer cells. Treatment of human breast cancer cells with cordycepin caused either apoptosis or persistent cell cycle arrest that was associated with reduced clonal growth of cordycepin-treated breast cancer cells. Highly de-differentiated breast cancer cell lines, such as MDA-MB-231 and MDA-MB-435, reacted more sensitive to cordycepin than less aggressive breast cancer cell lines (MCF7, T47D) or non-malignant breast epithelial cells (MCF10A), which poorly reacted to cordycepin. In cordycepin-sensitive breast cancer cells, a marked induction of the DNA damage response (DDR), including the phosphorylation of ATM, ATR, and histone ?H2AX could be observed. These data indicate that cordycepin, which was believed to cause cancer cell death by inhibition of RNA synthesis, induces DNA double strand breaks in breast cancer cells. The genotoxic effect of cordycepin on breast cancer cells indicates a new mechanism of cordycepin-induced cancer cell death, and its activity against highly undifferentiated breast cancer cells provides a new perspective of how cordycepin may be used in the treatment of advanced breast cancer. PMID:22821173

Lee, Hong Jue; Burger, Petra; Vogel, Marianne; Friese, Klaus; Brüning, Ansgar

2012-10-01

57

Heregulin Induces Transcriptional Activation of the Progesterone Receptor by a Mechanism That Requires Functional ErbB-2 and Mitogen-Activated Protein Kinase Activation in Breast Cancer Cells  

PubMed Central

The present study addresses the capacity of heregulin (HRG), a ligand of type I receptor tyrosine kinases, to transactivate the progesterone receptor (PR). For this purpose, we studied, on the one hand, an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in female BALB/c mice and, on the other hand, the human breast cancer cell line T47D. HRG was able to exquisitely regulate biochemical attributes of PR in a way that mimicked PR activation by progestins. Thus, HRG treatment of primary cultures of epithelial cells of the progestin-dependent C4HD murine mammary tumor line and of T47D cells induced a decrease of protein levels of PRA and -B isoforms and the downregulation of progesterone-binding sites. HRG also promoted a significant increase in the percentage of PR localized in the nucleus in both cell types. DNA mobility shift assay revealed that HRG was able to induce PR binding to a progesterone response element (PRE) in C4HD and T47D cells. Transient transfections of C4HD and T47D cells with a plasmid containing a PRE upstream of a chloramphenicol acetyltransferase (CAT) gene demonstrated that HRG promoted a significant increase in CAT activity. In order to assess the molecular mechanisms underlying PR transactivation by HRG, we blocked ErbB-2 expression in C4HD and T47D cells by using antisense oligodeoxynucleotides to ErbB-2 mRNA, which resulted in the abolishment of HRG's capacity to induce PR binding to a PRE, as well as CAT activity in the transient-transfection assays. Although the inhibition of HRG binding to ErbB-3 by an anti-ErbB-3 monoclonal antibody suppressed HRG-induced PR activation, the abolishment of HRG binding to ErbB-4 had no effect on HRG activation of PR. To investigate the role of mitogen-activated protein kinases (MAPKs), we used the selective MEK1/MAPK inhibitor PD98059. Blockage of MAPK activation resulted in complete abrogation of HRG's capacity to induce PR binding to a PRE, as well as CAT activity. Finally, we demonstrate here for the first time that HRG-activated MAPK can phosphorylate both human and mouse PR in vitro. PMID:12529413

Labriola, Leticia; Salatino, Mariana; Proietti, Cecilia J.; Pecci, Adali; Coso, Omar A.; Kornblihtt, Alberto R.; Charreau, Eduardo H.; Elizalde, Patricia V.

2003-01-01

58

Ectopic Production of Human Chorionic Gonadotrophin by Human Breast Tumours  

PubMed Central

The incidence of tumours ectopically producing the human chorionic gonadotrophins was studied in patients with breast cancer. Specific radioimmunoassay of subunits of HCG was utilized. Nine out of 65 patients with carcinoma of breast showed the presence of circulating HCG. Patients with other pathological conditions of breast tissue did not show any evidence of circulating HCG. PMID:4374964

Sheth, N. A.; Saruiya, J. N.; Ranadive, K. J.; Sheth, A. R.

1974-01-01

59

Microbiota of human breast tissue.  

PubMed

In recent years, a greater appreciation for the microbes inhabiting human body sites has emerged. In the female mammary gland, milk has been shown to contain bacterial species, ostensibly reaching the ducts from the skin. We decided to investigate whether there is a microbiome within the mammary tissue. Using 16S rRNA sequencing and culture, we analyzed breast tissue from 81 women with and without cancer in Canada and Ireland. A diverse population of bacteria was detected within tissue collected from sites all around the breast in women aged 18 to 90, not all of whom had a history of lactation. The principal phylum was Proteobacteria. The most abundant taxa in the Canadian samples were Bacillus (11.4%), Acinetobacter (10.0%), Enterobacteriaceae (8.3%), Pseudomonas (6.5%), Staphylococcus (6.5%), Propionibacterium (5.8%), Comamonadaceae (5.7%), Gammaproteobacteria (5.0%), and Prevotella (5.0%). In the Irish samples the most abundant taxa were Enterobacteriaceae (30.8%), Staphylococcus (12.7%), Listeria welshimeri (12.1%), Propionibacterium (10.1%), and Pseudomonas (5.3%). None of the subjects had signs or symptoms of infection, but the presence of viable bacteria was confirmed in some samples by culture. The extent to which these organisms play a role in health or disease remains to be determined. PMID:24610844

Urbaniak, Camilla; Cummins, Joanne; Brackstone, Muriel; Macklaim, Jean M; Gloor, Gregory B; Baban, Chwanrow K; Scott, Leslie; O'Hanlon, Deidre M; Burton, Jeremy P; Francis, Kevin P; Tangney, Mark; Reid, Gregor

2014-05-01

60

The Human Cell Surfaceome of Breast Tumors  

PubMed Central

Introduction. Cell surface proteins are ideal targets for cancer therapy and diagnosis. We have identified a set of more than 3700 genes that code for transmembrane proteins believed to be at human cell surface. Methods. We used a high-throuput qPCR system for the analysis of 573 cell surface protein-coding genes in 12 primary breast tumors, 8 breast cell lines, and 21 normal human tissues including breast. To better understand the role of these genes in breast tumors, we used a series of bioinformatics strategies to integrates different type, of the datasets, such as KEGG, protein-protein interaction databases, ONCOMINE, and data from, literature. Results. We found that at least 77 genes are overexpressed in breast primary tumors while at least 2 of them have also a restricted expression pattern in normal tissues. We found common signaling pathways that may be regulated in breast tumors through the overexpression of these cell surface protein-coding genes. Furthermore, a comparison was made between the genes found in this report and other genes associated with features clinically relevant for breast tumorigenesis. Conclusions. The expression profiling generated in this study, together with an integrative bioinformatics analysis, allowed us to identify putative targets for breast tumors. PMID:24195083

da Cunha, Julia Pinheiro Chagas; Galante, Pedro Alexandre Favoretto; de Souza, Jorge Estefano Santana; Pieprzyk, Martin; Carraro, Dirce Maria; Old, Lloyd J.; Camargo, Anamaria Aranha; de Souza, Sandro Jose

2013-01-01

61

Enhanced translational efficiency of a novel transforming growth factor beta 3 mRNA in human breast cancer cells.  

PubMed Central

The mRNA for transforming growth factor beta 3 (TGF-beta 3) includes a long (1.1-kb) 5' noncoding region which exerts a potent inhibitory effect on translational efficiency. We now report that many human breast cancer cell lines (T47-D, SK-BR-3, ZR-75-1, and BT-474) express two mRNA species for TGF-beta 3: the 3.5-kb transcript previously described as the only TGF-beta 3 mRNA species in cells and a novel 2.6-kb transcript which lacks approximately 870 nucleotides from the 5' noncoding region. The 5' end of the shorter transcript was sequenced, establishing it to be a 5' truncation of the full-length TGF-beta 3 transcript. Estradiol decreased mRNA levels of both TGF-beta 3 mRNA transcripts to an equivalent degree in estrogen receptor-positive cells. In contrast, the synthetic progestin gestodene altered the relative abundance of the two transcripts, preferentially diminishing the expression of the 2.6-kb transcript. The potential for enhanced mRNA translation attributable to the shorter 5' noncoding region was evaluated by transfection of cells with chimeric plasmid constructs in which the transcription unit consisted of coding sequence for chloramphenicol acetyltransferase downstream of the 5' noncoding sequence from TGF-beta 3. The translational efficiency of chloramphenicol acetyltransferase-encoding mRNA containing the shorter 5' noncoding region of the 2.6-kb TGF-beta 3 transcript was approximately seven times greater than with the full-length 5' noncoding region of TGF-beta 3. Polysome analysis of TGF-beta 3 mRNA in SK-BR-3 cells supported the hypothesis that the 2.6-kb transcript was more actively engaged in translation. Images PMID:8264630

Arrick, B A; Grendell, R L; Griffin, L A

1994-01-01

62

Retinoic acid reduces migration of human breast cancer cells: role of retinoic acid receptor beta.  

PubMed

Breast cancer is the most common malignancy in women and the appearance of distant metastases produces the death in 98% of cases. The retinoic acid receptor ? (RAR?) is not expressed in 50% of invasive breast carcinoma compared with normal tissue and it has been associated with lymph node metastasis. Our hypothesis is that RAR? protein participates in the metastatic process. T47D and MCF7 breast cancer cell lines were used to perform viability assay, immunobloting, migration assays, RNA interference and immunofluorescence. Administration of retinoic acid (RA) in breast cancer cells induced RAR? gene expression that was greatest after 72 hrs with a concentration 1 ?M. High concentrations of RA increased the expression of RAR? causing an inhibition of the 60% in cell migration and significantly decreased the expression of migration-related proteins [moesin, c-Src and focal adhesion kinase (FAK)]. The treatment with RAR? and RAR? agonists did not affect the cell migration. On the contrary, the addition of the selective retinoid RAR?-agonist (BMS453) significantly reduced cell migration comparable to RA inhibition. When RAR? gene silencing was performed, the RA failed to significantly inhibit migration and resulted ineffective to reduce moesin, c-Src and FAK expressions. RAR? is necessary to inhibit migration induced by RA in breast cancer cells modulating the expression of proteins involved in cell migration. PMID:24720764

Flamini, Marina Inés; Gauna, Gisel Valeria; Sottile, Mayra Lis; Nadin, Beatriz Silvina; Sanchez, Angel Matias; Vargas-Roig, Laura María

2014-06-01

63

Effects of biosurfactants on the viability and proliferation of human breast cancer cells.  

PubMed

Biosurfactants are molecules with surface activity produced by microorganisms that can be used in many biomedical applications. The anti-tumour potential of these molecules is being studied, although results are still scarce and few data are available regarding the mechanisms underlying such activity. In this work, the anti-tumour activity of a surfactin produced by Bacillus subtilis 573 and a glycoprotein (BioEG) produced by Lactobacillus paracasei subsp. paracasei A20 was evaluated. Both biosurfactants were tested against two breast cancer cell lines, T47D and MDA-MB-231, and a non-tumour fibroblast cell line (MC-3 T3-E1), specifically regarding cell viability and proliferation. Surfactin was found to decrease viability of both breast cancer cell lines studied. A 24 h exposure to 0.05 g l(-1) surfactin led to inhibition of cell proliferation as shown by cell cycle arrest at G1 phase. Similarly, exposure of cells to 0.15 g l(-1) BioEG for 48 h decreased cancer cells' viability, without affecting normal fibroblasts. Moreover, BioEG induced the cell cycle arrest at G1 for both breast cancer cell lines. The biosurfactant BioEG was shown to be more active than surfactin against the studied breast cancer cells. The results gathered in this work are very promising regarding the biosurfactants potential for breast cancer treatment and encourage further work with the BioEG glycoprotein. PMID:24949273

Duarte, Cristina; Gudiña, Eduardo J; Lima, Cristovao F; Rodrigues, Ligia R

2014-01-01

64

Effects of biosurfactants on the viability and proliferation of human breast cancer cells  

PubMed Central

Biosurfactants are molecules with surface activity produced by microorganisms that can be used in many biomedical applications. The anti-tumour potential of these molecules is being studied, although results are still scarce and few data are available regarding the mechanisms underlying such activity. In this work, the anti-tumour activity of a surfactin produced by Bacillus subtilis 573 and a glycoprotein (BioEG) produced by Lactobacillus paracasei subsp. paracasei A20 was evaluated. Both biosurfactants were tested against two breast cancer cell lines, T47D and MDA-MB-231, and a non-tumour fibroblast cell line (MC-3 T3-E1), specifically regarding cell viability and proliferation. Surfactin was found to decrease viability of both breast cancer cell lines studied. A 24 h exposure to 0.05 g l-1 surfactin led to inhibition of cell proliferation as shown by cell cycle arrest at G1 phase. Similarly, exposure of cells to 0.15 g l-1 BioEG for 48 h decreased cancer cells’ viability, without affecting normal fibroblasts. Moreover, BioEG induced the cell cycle arrest at G1 for both breast cancer cell lines. The biosurfactant BioEG was shown to be more active than surfactin against the studied breast cancer cells. The results gathered in this work are very promising regarding the biosurfactants potential for breast cancer treatment and encourage further work with the BioEG glycoprotein. PMID:24949273

2014-01-01

65

Modeling mixtures of environmental estrogens found in U.S. surface waters with an in vitro estrogen mediated transcriptionai activation assay (T47D-KBluc).  

EPA Science Inventory

There is growing concern of exposure to fish, wildlife, and humans to water sources contaminated with estrogens and the potential impact on reproductive health. Environmental estrogens can come from various sources including concentrated animal feedlot operations (CAFO), municipa...

66

The PIKfyve–ArPIKfyve–Sac3 triad in human breast cancer: Functional link between elevated Sac3 phosphatase and enhanced proliferation of triple negative cell lines  

SciTech Connect

Highlights: •We assess PAS complex proteins and phosphoinositide levels in breast cancer cells. •Sac3 and ArPIKfyve are markedly elevated in triple-negative breast cancer cells. •Sac3 silencing inhibits proliferation in triple-negative breast cancer cell lines. •Phosphoinositide profiles are altered in breast cancer cells. •This is the first evidence linking high Sac3 with breast cancer cell proliferation. -- Abstract: The phosphoinositide 5-kinase PIKfyve and 5-phosphatase Sac3 are scaffolded by ArPIKfyve in the PIKfyve–ArPIKfyve–Sac3 (PAS) regulatory complex to trigger a unique loop of PtdIns3P–PtdIns(3,5)P{sub 2} synthesis and turnover. Whereas the metabolizing enzymes of the other 3-phosphoinositides have already been implicated in breast cancer, the role of the PAS proteins and the PtdIns3P–PtdIns(3,5)P{sub 2} conversion is unknown. To begin elucidating their roles, in this study we monitored the endogenous levels of the PAS complex proteins in cell lines derived from hormone-receptor positive (MCF7 and T47D) or triple-negative breast cancers (TNBC) (BT20, BT549 and MDA-MB-231) as well as in MCF10A cells derived from non-tumorigenic mastectomy. We report profound upregulation of Sac3 and ArPIKfyve in the triple negative vs. hormone-sensitive breast cancer or non-tumorigenic cells, with BT cell lines showing the highest levels. siRNA-mediated knockdown of Sac3, but not that of PIKfyve, significantly inhibited proliferation of BT20 and BT549 cells. In these cells, knockdown of ArPIKfyve had only a minor effect, consistent with a primary role for Sac3 in TNBC cell proliferation. Intriguingly, steady-state levels of PtdIns(3,5)P{sub 2} in BT20 and T47D cells were similar despite the 6-fold difference in Sac3 levels between these cell lines. However, steady-state levels of PtdIns3P and PtdIns5P, both regulated by the PAS complex, were significantly reduced in BT20 vs. T47D or MCF10A cell lines, consistent with elevated Sac3 affecting directly or indirectly the homeostasis of these lipids in TNBC. Together, our results uncover an unexpected role for Sac3 phosphatase in TNBC cell proliferation. Database analyses, discussed herein, reinforce the involvement of Sac3 in breast cancer pathogenesis.

Ikonomov, Ognian C., E-mail: oikonomo@med.wayne.edu; Filios, Catherine, E-mail: cfilios@med.wayne.edu; Sbrissa, Diego, E-mail: dsbrissa@med.wayne.edu; Chen, Xuequn, E-mail: xchen@med.wayne.edu; Shisheva, Assia, E-mail: ashishev@med.wayne.edu

2013-10-18

67

Discovery of estrogen receptor ? target genes and response elements in breast tumor cells  

PubMed Central

Background Estrogens and their receptors are important in human development, physiology and disease. In this study, we utilized an integrated genome-wide molecular and computational approach to characterize the interaction between the activated estrogen receptor (ER) and the regulatory elements of candidate target genes. Results Of around 19,000 genes surveyed in this study, we observed 137 ER-regulated genes in T-47D cells, of which only 89 were direct target genes. Meta-analysis of heterogeneous in vitro and in vivo datasets showed that the expression profiles in T-47D and MCF-7 cells are remarkably similar and overlap with genes differentially expressed between ER-positive and ER-negative tumors. Computational analysis revealed a significant enrichment of putative estrogen response elements (EREs) in the cis-regulatory regions of direct target genes. Chromatin immunoprecipitation confirmed ligand-dependent ER binding at the computationally predicted EREs in our highest ranked ER direct target genes, NRIP1, GREB1 and ABCA3. Wider examination of the cis-regulatory regions flanking the transcriptional start sites showed species conservation in mouse-human comparisons in only 6% of predicted EREs. Conclusions Only a small core set of human genes, validated across experimental systems and closely associated with ER status in breast tumors, appear to be sufficient to induce ER effects in breast cancer cells. That cis-regulatory regions of these core ER target genes are poorly conserved suggests that different evolutionary mechanisms are operative at transcriptional control elements than at coding regions. These results predict that certain biological effects of estrogen signaling will differ between mouse and human to a larger extent than previously thought. PMID:15345050

Lin, Chin-Yo; Ström, Anders; Vega, Vinsensius Berlian; Li Kong, Say; Li Yeo, Ai; Thomsen, Jane S; Chan, Wan Ching; Doray, Balraj; Bangarusamy, Dhinoth K; Ramasamy, Adaikalavan; Vergara, Liza A; Tang, Suisheng; Chong, Allen; Bajic, Vladimir B; Miller, Lance D; Gustafsson, Jan-Åke; Liu, Edison T

2004-01-01

68

RAD50 targeting impairs DNA damage response and sensitizes human breast cancer cells to cisplatin therapy.  

PubMed

In tumor cells the effectiveness of anti-neoplastic agents that cause cell death by induction of DNA damage is influenced by DNA repair activity. RAD50 protein plays key roles in DNA double strand breaks repair (DSBs), which is crucial to safeguard genome integrity and sustain tumor suppression. However, its role as a potential therapeutic target has not been addressed in breast cancer. Our aim in the present study was to analyze the expression of RAD50 protein in breast tumors, and evaluate the effects of RAD50-targeted inhibition on the cytotoxicity exerted by cisplatin and anthracycline and taxane-based therapies in breast cancer cells. Immunohistochemistry assays on tissue microarrays indicate that the strong staining intensity of RAD50 was reduced in 14% of breast carcinomas in comparison with normal tissues. Remarkably, RAD50 silencing by RNA interference significantly enhanced the cytotoxicity of cisplatin. Combinations of cisplatin with doxorubicin and paclitaxel drugs induced synergistic effects in early cell death of RAD50-deficient MCF-7, SKBR3, and T47D breast cancer cells. Furthermore, we found an increase in the number of DSBs, and delayed phosphorylation of histone H2AX after cisplatin treatment in RAD50-silenced cells. These cellular events were associated to a dramatical increase in the frequency of chromosomal aberrations and a decrease of cell number in metaphase. In conclusion, our data showed that RAD50 abrogation impairs DNA damage response and sensitizes breast cancer cells to cisplatin-combined therapies. We propose that the development and use of inhibitors to manipulate RAD50 levels might represent a promising strategy to sensitize breast cancer cells to DNA damaging agents. PMID:24642965

Flores-Pérez, Ali; Rafaelli, Lourdes E; Ramírez-Torres, Nayeli; Aréchaga-Ocampo, Elena; Frías, Sara; Sánchez, Silvia; Marchat, Laurence A; Hidalgo-Miranda, Alfredo; Quintanar-Jurado, Valeria; Rodríguez-Cuevas, Sergio; Bautista-Piña, Verónica; Carlos-Reyes, Angeles; López-Camarillo, César

2014-06-01

69

Systems consequences of amplicon formation in human breast cancer  

E-print Network

Chromosomal structural variations play an important role in determining the transcriptional landscape of human breast cancers. To assess the nature of these structural variations, we analyzed eight breast tumor samples ...

Inaki, Koichiro

70

The molecular landscape of the normal human breast - defining normal  

PubMed Central

A key approach in understanding how breast cancer can occur is to determine the regulatory pathways at play in the normal breast and to identify precisely the normal developmental mechanisms subverted during early breast cancer progression. Using normal human breast tissue samples, Pardo and colleagues have identified the gene targets and pathways displaying fluctuating expression as a consequence of the menstrual cycle. Detailed characterization of how the human breast functions in its normal state, and how this may be perturbed at its earliest point, will provide a critical step toward the prevention of breast cancer.

2014-01-01

71

Chemical Biomarkers of Human Breast Milk Pollution  

PubMed Central

Human milk is, without question, the best source of nutrition for infants containing the optimal balance of fats, carbohydrates and proteins for developing babies. Breastfeeding provides a range of benefits for growth, immunity and development building a powerful bond between mother and her child. Recognition of the manifold benefits of breast milk has led to the adoption of breast-feeding policies by numerous health and professional organizations such as the World Health Organization and American Academy of Pediatrics. In industrially developed as well as in developing nations, human milk contamination by toxic chemicals such as heavy metals, dioxins and organohalogen compounds, however, is widespread and is the consequence of decades of inadequately controlled pollution. Through breastfeeding, the mother may transfer to the suckling infant potentially toxic chemicals to which the mother has previously been exposed. In the present review, environmental exposure, acquisition and current levels of old and emerging classes of breast milk pollutants are systematically presented. Although scientific evidences indicated that the advantages of breast-feeding outweigh any risks from contaminants, it is important to identify contaminant trends, to locate disproportionately exposed populations, and to take public health measures to improve chemical BM pollution as possible. PMID:19578503

Massart, Francesco; Gherarducci, Giulia; Marchi, Benedetta; Saggese, Giuseppe

2008-01-01

72

Immunoreactive opioid peptides in human breast cancer.  

PubMed Central

Opioid peptides have a variety of actions on inter alia pituitary hormone secretion and the immune system. Release of endogenous opioids has been found to stimulate growth of experimental breast cancers and opiate receptor blockers have reduced the growth of chemically induced rat breast tumors. Opioid peptides may therefore play a role in human breast cancer. Invasive ductal carcinomas from 61 premenopausal women were immunocytochemically analyzed for the presence of opioid peptide immunoreactivity. Positive staining was unambiguously identified in 34 of the tumors (56%). In addition, a medullary carcinoma was positive. In a smaller series of tumors, opioid peptide immunoreactive cells were detected in both primary tumors and metastases. Positive tumor cells were usually few and scattered. Therefore, underestimates of their true frequency of occurrence are likely to have occurred, making accurate correlations with clinical behavior and estrogen receptor status difficult. No correlations with estrogen receptors were established for the unambiguously opioid peptide-positive tumors. Many of the positive tumors also stained with antibodies to gamma-endorphin and alpha-melanocyte-stimulating hormone, suggesting the presence of proopiomelanocortin-derived peptides in them. However, peptides derived from other opioid precursors also may be present in breast cancer. Images Figure 1 PMID:2464945

Scopsi, L.; Balslev, E.; Brunner, N.; Poulsen, H. S.; Andersen, J.; Rank, F.; Larsson, L. I.

1989-01-01

73

Altered expression of the DNA repair protein, N-methylpurine-DNA glycosylase (MPG), in breast cancer  

Microsoft Academic Search

We examined expression of N-methylpurine-DNA glycosylase (MPG), a DNA repair enzyme that removes N-alkylpurine damage, in normal, malignant, and immortalized breast epithelial cells, and breast cancer cell lines (MDA-MB-231, MCF7, T47D). Northern analysis showed increased expression in cancer versus normal breast epithelial cells (2–24-fold). Southern blots revealed no gene amplification or polymorphisms. Immunofluorescence, immunohistochemistry, and Western blot analysis demonstrated increased

Sonia R Cerda; Patrick W Turk; Ann D Thor; Sigmund A Weitzman

1998-01-01

74

Oestrogen Metabolism in Cultured Human Breast Tumours  

PubMed Central

The interconversion of tritium labelled oestrone and oestradiol-17? has been investigated in human breast tumours maintained in organ culture for 3 days. Benign tumours were significantly different from scirrhous carcinomata both in the concentration of radioactivity taken up by the tissue and in the ratios of oestradiol-17?/oestrone achieved. The fact that malignant tumours were able to convert oestrone to oestradiol-17? is of interest in view of the relatively high plasma levels of oestrone in post-menopausal women. ImagesFig. 1Fig. 2Fig. 3Fig. 4 PMID:4345953

Willcox, P. A.; Thomas, G. H.

1972-01-01

75

Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation.  

PubMed

The process of cancer cell invasion involves degradation of the extracellular matrix (ECM) by proteases, integrin adhesion and cell motility. The role of ECM degrading proteases on the hypoxia-induced invasion of breast carcinoma cells was investigated. Hypoxia markedly increased the invasion capacity of MDA-MB-231 and MDA-MB-435 breast carcinoma cell lines. Matrix metalloproteinase (MMP) inhibitors blocked the hypoxia-induced invasion, whereas other protease inhibitors had no effect. Antibodies or siRNAs blocking either membrane type-1 MMP (MT1-MMP) or MMP-2 were effective in reducing the hypoxia-induced invasion. Serum-free reconstitution experiments confirmed the involvement of the MT1-MMP/MMP-2/tissue inhibitor of metalloproteinase-2 complex in this hypoxia-induced response. Overexpression of MT1-MMP in a poorly invasive breast cancer cell line, T47-D, promoted hypoxia-induced invasion and MMP-2 activation. Cell surface accumulation and activation of MT1-MMP without apparent regulation at the mRNA or protein levels indicated a post-translational adaptive response to hypoxia. Inhibition of the small GTPase RhoA eliminated the hypoxia-induced invasion and blocked the localization of MT1-MMP to the plasma membrane. Zymographic and molecular analysis of human breast tumors showed a strong correlation between hypoxic microenvironments and MMP-2 activation without changes in MT1-MMP expression. Our studies suggest that hypoxic tumor microenvironments promote breast cancer invasion through an MT1-MMP-dependent mechanism. PMID:16369494

Muñoz-Nájar, U M; Neurath, K M; Vumbaca, F; Claffey, K P

2006-04-13

76

Secretion of immunoreactive calcitonin by human breast carcinomas.  

PubMed Central

Twenty-three out of 28 patients with metastatic breast carcinoma and one out of 13 patients with localised disease had raised levels of plasma immunoreactive calcitonin. Monolayer cultures of breast carcinomas maintained for up to 10 weeks released immunoreactive calcitonin, and a primary breast carcinoma passaged in "nude" mice for over a year contained material immunologically and chromatographically resembling the monomeric form of human calcitonin. These studies indicate that breast carcinomas can produce calcitonin and that plasma calcitonin measurements may be useful in staging patients with breast carcinomas. PMID:1191996

Coombes, R C; Easty, G C; Detre, S I; Hillyard, C J; Stevens, U; Girgis, S I; Galante, L S; Heywood, L; Macintyre, I; Neville, A M

1975-01-01

77

TNF{alpha} acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK, Akt and NF-{kappa}B-dependent pathways  

SciTech Connect

Tumor necrosis factor {alpha} (TNF{alpha}) enhances proliferation of chemically-induced mammary tumors and of T47D human cell line through not fully understood pathways. Here, we explored the intracellular signaling pathways triggered by TNF{alpha}, the participation of TNF{alpha} receptor (TNFR) 1 and TNFR2 and the molecular mechanism leading to breast cancer growth. We demonstrate that TNF{alpha} induced proliferation of C4HD murine mammary tumor cells and of T47D cells through the activation of p42/p44 MAPK, JNK, PI3-K/Akt pathways and nuclear factor-kappaB (NF-{kappa}B) transcriptional activation. A TNF{alpha}-specific mutein selectively binding to TNFR1 induced p42/p44 MAPK, JNK, Akt activation, NF-{kappa}B transcriptional activation and cell proliferation, just like wild-type TNF{alpha}, while a mutein selective for TNFR2 induced only p42/p44 MAPK activation. Interestingly, blockage of TNFR1 or TNFR2 with specific antibodies was enough to impair TNF{alpha} signaling and biological effect. Moreover, in vivo TNF{alpha} administration supported C4HD tumor growth. We also demonstrated, for the first time, that injection of a selective inhibitor of NF-{kappa}B activity, Bay 11-7082, resulted in regression of TNF{alpha}-promoted tumor. Bay 11-7082 blocked TNF{alpha} capacity to induce cell proliferation and up-regulation of cyclin D1 and of Bcl-x{sub L}in vivo and in vitro. Our results reveal evidence for TNF{alpha} as a breast tumor promoter, and provide novel data for a future therapeutic approach using TNF{alpha} antagonists and NF-{kappa}B pharmacological inhibitors in established breast cancer treatment.

Rivas, Martin A.; Carnevale, Romina P.; Proietti, Cecilia J.; Rosemblit, Cinthia; Beguelin, Wendy; Salatino, Mariana; Charreau, Eduardo H. [Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biologia y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Buenos Aires, C1428ADN (Argentina); Frahm, Isabel [Servicio de Patologia, Sanatorio Mater Dei, Buenos Aires (Argentina); Sapia, Sandra [Laboratorio de Patologia, Fundaleu, Buenos Aires (Argentina); Brouckaert, Peter [Department of Molecular Biomedical Research, VIB and Ghent University, Ghent (Belgium); Elizalde, Patricia V. [Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biologia y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Buenos Aires, C1428ADN (Argentina); Schillaci, Roxana [Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biologia y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Buenos Aires, C1428ADN (Argentina)], E-mail: rschilla@dna.uba.ar

2008-02-01

78

Prolactin Synthesis and Secretion by Human Breast Cancer Cells  

Microsoft Academic Search

A possible autocrine function of prolactin (Prl) in human breast cancer was explored by the addition of a panel of anti-human Prl inAlis to T47Dco and MCF7 human breast adenocarcinoma cells, inAb 631 and niAh 390 inhibited cell growth by 86 and 68%, respectively, in the estrogen receptor-negative T47Dco cells and by 20 and 71%, respectively, in the estrogen receptor-positive

Erika Ginsburg; Barbara K. Vonderhaar

79

Inhibition of Mus81 by siRNA enhances sensitivity to 5-FU in breast carcinoma cell lines  

PubMed Central

Purpose One of the most challenging aspects of breast carcinoma chemotherapy is the rapid acquirement of drug resistance. Improving the sensitivity to chemotherapeutic drugs is very important for successful treatment. Mus81 plays an important role in maintaining the stability of the genome and DNA repair. However, recent studies suggested that Mus81 expression levels correlate well with resistance to DNA-damaging drugs. The present study aimed to investigate the role of Mus81 on the chemosensitivity of breast carcinoma cells in response to 5-fluorouracil (5-FU), a chemotherapeutic drug that is widely used for treatment of breast malignancies. Methods The expression of Mus81 in MCF-7 and T47D cells was suppressed by small interfering RNA (siRNA). mRNA and protein levels of Mus81 were analyzed by quantitative real-time polymerase chain reaction and Western blot. Cell viability and colony survival were determined by Cell Counting Kit-8 and plate colony formation assay, respectively. Cell cycle and apoptosis were detected by flow cytometry. Results 5-FU inhibited the cell viability of MCF-7 and T47D cells in a concentration-dependent manner. We found that the Mus81-silenced MCF-7 and T47D cells exhibited decreased cell viability and clonogenic survival, but increased G2 accumulation, in response to 5-FU. In addition, Mus81 deficiency resulted in increased apoptosis and p53 expression in MCF-7 after 5-FU treatment. However, Mus81 deficiency did not affect the apoptosis of T47D cells with 5-FU. Conclusion Taken together, our data suggest that Mus81 inhibition significantly increased the chemosensitivity of MCF-7 and T47D cells in response to 5-FU. Thus, Mus81 siRNA is potentially a useful adjuvant strategy for breast cancer chemotherapy. PMID:25364260

Qian, Ying; Liu, Yanning; Yan, Qiuyue; Lv, Juan; Ni, Xiaoyan; Wu, Yunlu; Dong, Xuejun

2014-01-01

80

Microbial Dysbiosis Is Associated with Human Breast Cancer  

PubMed Central

Breast cancer affects one in eight women in their lifetime. Though diet, age and genetic predisposition are established risk factors, the majority of breast cancers have unknown etiology. The human microbiota refers to the collection of microbes inhabiting the human body. Imbalance in microbial communities, or microbial dysbiosis, has been implicated in various human diseases including obesity, diabetes, and colon cancer. Therefore, we investigated the potential role of microbiota in breast cancer by next-generation sequencing using breast tumor tissue and paired normal adjacent tissue from the same patient. In a qualitative survey of the breast microbiota DNA, we found that the bacterium Methylobacterium radiotolerans is relatively enriched in tumor tissue, while the bacterium Sphingomonas yanoikuyae is relatively enriched in paired normal tissue. The relative abundances of these two bacterial species were inversely correlated in paired normal breast tissue but not in tumor tissue, indicating that dysbiosis is associated with breast cancer. Furthermore, the total bacterial DNA load was reduced in tumor versus paired normal and healthy breast tissue as determined by quantitative PCR. Interestingly, bacterial DNA load correlated inversely with advanced disease, a finding that could have broad implications in diagnosis and staging of breast cancer. Lastly, we observed lower basal levels of antibacterial response gene expression in tumor versus healthy breast tissue. Taken together, these data indicate that microbial DNA is present in the breast and that bacteria or their components may influence the local immune microenvironment. Our findings suggest a previously unrecognized link between dysbiosis and breast cancer which has potential diagnostic and therapeutic implications. PMID:24421902

Xuan, Caiyun; Shamonki, Jaime M.; Chung, Alice; DiNome, Maggie L.; Chung, Maureen; Sieling, Peter A.; Lee, Delphine J.

2014-01-01

81

Human Breast Milk Provides Better Antioxidant Capacity than Infant Formula  

PubMed Central

Human milk contains all of the constituents that are required for the optimal growth and development of a neonate. It supports the development of brain, immune, and physiological systems. This study aimed to consider the significance of breast milk in preventing oxidative stress by comparing total antioxidant capacity (TAC) in breast and formula milk for premature infants, demonstrating the relationship between TAC in breast milk and postnatal age in days. The Ferric reducing antioxidant power assay (FRAP) method was used to spectophotometrically measure of TAC in breast and formula milk. One hundred and fourty (n = 140) lactating mothers agreed to participate in the study. TAC was also measured in two brands of formula milk (n = 80). The Range of TAC in human breast milk was 234.27-1442.31 ?M and in two formula was 160.04-630.92 ?M. The average TAC was significantly higher in breast milk (642.94 ± 241.23 ?M) compared to formula milk (280.986 ± 100.34 ?M) p < 0.0001. The TAC of breast milk was increased with some nutritional parameter such as increased consumption of cheese, vegetables, fruits, bread and nuts. Infants’ height at the birthday was directly correlated with antioxidant capacity of breast milk, whilst a reversed correlation was observed between TAC in breast milk and infant age. Based on our results, it is concluded that the TAC of breast milk is varied and affected by nutrition. It is alo observed that TAC is significantly higher in breast milk than formula, which means that breast milk provides better antioxidant potency than infant formula. PMID:24381611

Oveisi, Mohammad Reza; Sadeghi, Naficeh; Jannat, Behrooz; Hajimahmoodi, Mannan; Behfar, Abd-ol-Azim; Jannat, Forouzandeh; MokhtariNasab, Fariba

2010-01-01

82

Possible DNA Viral Factors of Human Breast Cancer  

PubMed Central

Viruses are considered to be one of the high-risk factors closely related to human breast cancer. However, different studies of viruses in breast cancer present conflicting results and some of these works remain in dispute. DNA viruses, such as specific types of human papillomaviruses (HPV), Epstein–Barr virus (EBV), human cytomegalovirus (HCMV), herpes simplex virus (HSV), and human herpes virus type 8 (HHV-8), have emerged as causal factors of some human cancers. These respective exogenous viruses and the possibility of multiple viral factors are discussed in this review. PMID:24281079

Hsu, Chun-Ru; Lu, Tsong-Ming; Chin, Lengsu William; Yang, Chi-Chiang

2010-01-01

83

Calmodulin modulates Akt activity in human breast cancer cell lines  

Microsoft Academic Search

Growth factor-induced activation of Akt occurs in the majority of human breast cancer cell lines resulting in a variety of\\u000a cellular outcomes, including suppression of apoptosis and enhanced survival. We demonstrate that epidermal growth factor (EGF)-initiated\\u000a activation of Akt is mediated by the ubiquitous calcium sensing molecule, calmodulin, in the majority of human breast cancer\\u000a cell lines. Specifically, in estrogen

Christine M. Coticchia; Chetana M. Revankar; Tushar B. Deb; Robert B. Dickson; Michael D. Johnson

2009-01-01

84

Evaluation of in vitro methods for detecting the effects of various chemicals on the human progesterone receptor, with a focus on pyrethroid insecticides.  

PubMed

The progesterone receptor (PR) is associated with physiological events such as implantation and the maintenance of pregnancy. Recently, it has become a social concern that chemicals may exert agonistic or antagonistic effects on hormone receptors. Therefore, we examined the effects of various chemicals on the human PR, with a focus on pyrethroid insecticides, using three in vitro methods. Eight pyrethroid insecticides (fenvalerate, d-allethrin, d-phenothrin, prallethrin, empenthrin, permethrin, cypermethrin and imiprothrin), examples of environmental pollutants and positive control chemicals were subjected to a reporter gene assay (luciferase assay) using human breast cancer T-47D cells, a two-hybrid assay and a binding assay using the same whole cells or receptors (cell-free). In none of these did the eight pyrethroid insecticides show any binding to the PR, agonistic or antagonistic effects. PMID:11137321

Sumida, K; Saito, K; Ooe, N; Isobe, N; Kaneko, H; Nakatsuka, I

2001-01-01

85

Bovine Leukemia Virus DNA in Human Breast Tissue  

PubMed Central

Bovine leukemia virus (BLV), a deltaretrovirus, causes B-cell leukemia/lymphoma in cattle and is prevalent in herds globally. A previous finding of antibodies against BLV in humans led us to examine the possibility of human infection with BLV. We focused on breast tissue because, in cattle, BLV DNA and protein have been found to be more abundant in mammary epithelium than in lymphocytes. In human breast tissue specimens, we identified BLV DNA by using nested liquid-phase PCR and DNA sequencing. Variations from the bovine reference sequence were infrequent and limited to base substitutions. In situ PCR and immunohistochemical testing localized BLV to the secretory epithelium of the breast. Our finding of BLV in human tissues indicates a risk for the acquisition and proliferation of this virus in humans. Further research is needed to determine whether BLV may play a direct role in human disease. PMID:24750974

Shen, Hua Min; Jensen, Hanne M.; Choi, K. Yeon; Sun, Dejun; Nuovo, Gerard

2014-01-01

86

Studies of human breast cancer metastasis using nude mice  

Microsoft Academic Search

Athymic nude mice have been used in recent years to study the biology of human tumors and to assess therapeutic responses in vivo rather than just in vitro. Some human tumors metastasize in nude mice, providing model systems for analyzing various aspects of the metastatic phenotype of human neoplasms. For breast carcinomas, however, the tumor-take rate of surgical specimens is

Janet E. Price; Ruo Dan Zhang

1990-01-01

87

Extra-Nuclear Signalling of Estrogen Receptor to Breast Cancer Cytoskeletal Remodelling, Migration and Invasion  

PubMed Central

Background Estrogen is an established enhancer of breast cancer development, but less is known on its effect on local progression or metastasis. We studied the effect of estrogen receptor recruitment on actin cytoskeleton remodeling and breast cancer cell movement and invasion. Moreover, we characterized the signaling steps through which these actions are enacted. Methodology/Principal Findings In estrogen receptor (ER) positive T47-D breast cancer cells ER activation with 17?-estradiol induces rapid and dynamic actin cytoskeleton remodeling with the formation of specialized cell membrane structures like ruffles and pseudopodia. These effects depend on the rapid recruitment of the actin-binding protein moesin. Moesin activation by estradiol depends on the interaction of ER? with the G protein G?13, which results in the recruitment of the small GTPase RhoA and in the subsequent activation of its downstream effector Rho-associated kinase-2 (ROCK-2). ROCK-2 is responsible for moesin phosphorylation. The G?13/RhoA/ROCK/moesin cascade is necessary for the cytoskeletal remodeling and for the enhancement of breast cancer cell horizontal migration and invasion of three-dimensional matrices induced by estrogen. In addition, human samples of normal breast tissue, fibroadenomas and invasive ductal carcinomas show that the expression of wild-type moesin as well as of its active form is deranged in cancers, with increased protein amounts and a loss of association with the cell membrane. Conclusions/Significance These results provide an original mechanism through which estrogen can facilitate breast cancer local and distant progression, identifying the extra-nuclear G?13/RhoA/ROCK/moesin signaling cascade as a target of ER? in breast cancer cells. This information helps to understand the effects of estrogen on breast cancer metastasis and may provide new targets for therapeutic interventions. PMID:18493596

Giretti, Maria Silvia; Fu, Xiao-Dong; De Rosa, Giovanni; Sarotto, Ivana; Baldacci, Chiara; Garibaldi, Silvia; Mannella, Paolo; Biglia, Nicoletta; Sismondi, Piero; Genazzani, Andrea Riccardo; Simoncini, Tommaso

2008-01-01

88

Lipids status in human breast cyst fluids  

Microsoft Academic Search

Benign mammary gross cystic disease is the most common breast lesion; women with apocrine changes of epithelium lining the cysts are at higher risk for developing breast cancer than the normal population. Total cholesterol, high- and low-density lipoproteins fractions, triglycerides and phospholipids, lipase activity and total lipid concentrations were measured in cyst fluids and sera from 89 women affected by

F. Mannello; G. D. Bocchiotti; F. Pignatti Morano; L. M. Fratepietro; G. Gazzanelli

1996-01-01

89

Human breast duct anatomy, the ‘sick lobe’ hypothesis and intraductal approaches to breast cancer  

Microsoft Academic Search

SummaryIntroduction  Information about central and peripheral duct anatomy is a requirement for developing intraductal approaches to human breast cancer, but remains sparse. This study looks at the acquisition and digital modelling of data describing breast duct branching from thick (‘subgross’) sections using data structures from the neurosciences, and at high-throughput imaging of duct anatomy in the nipple.Methods  The branching of a large

James J. Going; Timothy J. Mohun

2006-01-01

90

Localization of BRCA1 Protein in Human Breast Cancer Cells  

Microsoft Academic Search

There is still an ongoing debate concerning the cellular localization of BRCA1 protein in breast cancer. To address this question, we compared the localization of BRCA1 protein using several monoclonal (Ab-1) or polyclonal (C20, D20, I20) antibodies under different technical conditions on human breast cancer cell lines. We worked on the fixation and permeabilization conditions in order to preserve the

Monique Chambon; Philippe Nirdé; Michel Gleizes; Pascal Roger; Françoise Vignon

2003-01-01

91

Siah1 proteins enhance radiosensitivity of human breast cancer cells  

Microsoft Academic Search

BACKGROUND: Siah proteins play an important role in cancer progression. We evaluated the effect of Siah1, its splice variants Siah1L and the Siah1 mutant with the RING finger deleted (Siah1?R) on radiosensitization of human breast cancer cells. METHODS: The status of Siah1 and Siah1L was analysed in five breast cancer cell lines. To establish stable cells, SKBR3 cells were transfected

Hai-Tao He; Emmanouil Fokas; An You; Rita Engenhart-Cabillic; Han-Xiang An

2010-01-01

92

Comprehensive molecular portraits of human breast tumours.  

PubMed

We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer. PMID:23000897

2012-10-01

93

Expression of transcripts of interleukin-6 and related cytokines by human breast tumors, breast cancer cells, and adipose stromal cells  

Microsoft Academic Search

The expression of transcripts of cytokines of the interleukin-6 (IL-6) family has been examined in human breast tumors, breast cancer cell lines, and adipose stromal cells, by means of reverse transcription polymerase chain reaction amplification. Of the six breast tumor samples examined, all expressed transcripts encoding IL-6 and Leukemia Inhibitory Factor (LIF). Four of the samples also expressed transcripts for

Miranda B Crichton; John E Nichols; Ying Zhao; Serdar E Bulun; Evan R Simpson

1996-01-01

94

The Oncogenic Potential of Human Cytomegalovirus and Breast Cancer  

PubMed Central

Breast cancer is the leading causes of cancer-related death among women. The vast majority of breast cancers are carcinomas that originate from cells lining the milk-forming ducts of the mammary gland. Numerous articles indicate that breast tumors exhibit diverse phenotypes depending on their distinct physiopathological signatures, clinical courses, and therapeutic possibilities. The human cytomegalovirus (HCMV) is a multifaceted highly host specific betaherpesvirus that is regarded as asymptomatic or mildly pathogenic virus in immunocompetent host. HCMV may cause serious in utero infections as well as acute and chronic complications in immunocompromised individual. The involvement of HCMV in late inflammatory complications underscores its possible role in inflammatory diseases and cancer. HCMV targets a variety of cell types in vivo, including macrophages, epithelial cells, endothelial cells, fibroblasts, stromal cells, neuronal cells, smooth muscle cells, and hepatocytes. HCMV can be detected in the milk after delivery and thereby HCMV could spread to adjacent mammary epithelial cells. HCMV also infects macrophages and induces an atypical M1/M2 phenotype, close to the tumor-associated macrophage phenotype, which is associated with the release of cytokines involved in cancer initiation or promotion and breast cancer of poor prognosis. HCMV antigens and DNA have been detected in tissue biopsies of breast cancers and elevation in serum HCMV IgG antibody levels has been reported to precede the development of breast cancer in some women. In this review, we will discuss the potential role of HCMV in the initiation and progression of breast cancer.

Herbein, Georges; Kumar, Amit

2014-01-01

95

CHL1 is involved in human breast tumorigenesis and progression  

SciTech Connect

Highlights: •CHL1 is down-regulation in breast cancer tissues. •Down-regulation of CHL1 is related to high grade. •Overexpression of CHL1 inhibits breast cancer cell proliferation and invasion in vitro. •CHL1 deficiency induces breast cancer cell proliferation and invasion both in vitro and in vivo. -- Abstract: Neural cell adhesion molecules (CAM) play important roles in the development and regeneration of the nervous system. The L1 family of CAMs is comprised of L1, Close Homolog of L1 (CHL1, L1CAM2), NrCAM, and Neurofascin, which are structurally related trans-membrane proteins in vertebrates. Although the L1CAM has been demonstrated play important role in carcinogenesis and progression, the function of CHL1 in human breast cancer is limited. Here, we found that CHL1 is down-regulated in human breast cancer and related to lower grade. Furthermore, overexpression of CHL1 suppresses proliferation and invasion in MDA-MB-231 cells and knockdown of CHL1 expression results in increased proliferation and invasion in MCF7 cells in vitro. Finally, CHL1 deficiency promotes tumor formation in vivo. Our results may provide a strategy for blocking breast carcinogenesis and progression.

He, Li-Hong [Medical Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China) [Medical Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Ma, Qin [Department of Oncology, The General Hospital of Tianjin Medical University, Tianjin (China)] [Department of Oncology, The General Hospital of Tianjin Medical University, Tianjin (China); Shi, Ye-Hui [Medical Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China) [Medical Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Ge, Jie; Zhao, Hong-Meng [Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China) [Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Li, Shu-Fen [Medical Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China) [Medical Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Tong, Zhong-Sheng, E-mail: 83352162@qq.com [Medical Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China) [Medical Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China)

2013-08-23

96

Stearate Preferentially Induces Apoptosis in Human Breast Cancer Cells  

PubMed Central

Stearic acid (stearate) is an 18-carbon saturated fatty acid that has been shown to inhibit invasion and proliferation and induce apoptosis in various human cell types. The specificity of stearate-induced apoptosis for cancerous versus non-cancerous breast cells has not been examined and the mechanism underlying stearate-induced apoptosis is unknown. Morphological analysis, cell viability and caspase-3 activity assays demonstrated that stearate activated apoptosis preferentially in cancerous breast cells in a time and dose dependent manner. Inhibition of de novo diacylgycerol synthesis or protein kinase C (PKC) blocked stearate-induced caspase-3 activity, indicating the involvement of a novel or classical PKC isozyme. To our knowledge this is the first study showing that stearate induces apoptosis preferentially in breast cancer cells and implicates protein kinase C in the signaling cascade. These results raise the possibility of dietary stearate having a beneficial role in the prevention or treatment of breast cancer. PMID:19838949

Evans, Lynda M.; Cowey, Stephanie L.; Siegal, Gene P.; Hardy, Robert W.

2010-01-01

97

Human neural stem cell tropism to metastatic breast cancer.  

PubMed

Metastasis to multiple organs is the primary cause of mortality in breast cancer patients. The poor prognosis for patients with metastatic breast cancer and toxic side effects of currently available treatments necessitate the development of effective tumor-selective therapies. Neural stem cells (NSCs) possess inherent tumor tropic properties that enable them to overcome many obstacles of drug delivery that limit effective chemotherapy strategies for breast cancer. We report that increased NSC tropism to breast tumor cell lines is strongly correlated with the invasiveness of cancer cells. Interleukin 6 (IL-6) was identified as a major cytokine mediating NSC tropism to invasive breast cancer cells. We show for the first time in a preclinical mouse model of metastatic human breast cancer that NSCs preferentially target tumor metastases in multiple organs, including liver, lung, lymph nodes, and femur, versus the primary intramammary fat pad tumor. For proof-of-concept of stem cell-mediated breast cancer therapy, NSCs were genetically modified to secrete rabbit carboxylesterase (rCE), an enzyme that activates the CPT-11 prodrug to SN-38, a potent topoisomerase I inhibitor, to effect tumor-localized chemotherapy. In vitro data demonstrate that exposure of breast cancer cells to conditioned media from rCE-secreting NSCs (NSC.rCE) increased their sensitivity to CPT-11 by 200-fold. In vivo, treatment of tumor-bearing mice with NSC.rCE cells in combination with CPT-11 resulted in reduction of metastatic tumor burden in lung and lymph nodes. These data suggest that NSC-mediated enzyme/prodrug therapy may be more effective and less toxic than currently available chemotherapy strategies for breast cancer metastases. PMID:22084033

Zhao, Donghong; Najbauer, Joseph; Annala, Alexander J; Garcia, Elizabeth; Metz, Marianne Z; Gutova, Margarita; Polewski, Monika D; Gilchrist, Megan; Glackin, Carlotta A; Kim, Seung U; Aboody, Karen S

2012-02-01

98

Ron Receptor Tyrosine Kinase Activation Confers Resistance to Tamoxifen in Breast Cancer Cell Lines1  

PubMed Central

Although tamoxifen treatment is associated with improved survival in patients with estrogen receptor (ER)-positive breast tumors, resistance remains an important clinical obstacle. Signaling through growth factor signaling pathways, in particular through receptor tyrosine kinases, has been demonstrated to confer tamoxifen resistance in an estradiol-independent manner. The Ron receptor tyrosine kinase, a member of the c-Met family of receptors, is expressed in a number of human epithelial tumors, and elevated expression of Ron is associated with poor prognosis in women with breast cancer. In this report, we evaluated the role of Ron receptor activation in conferring resistance to tamoxifen in human and murine breast cancer cell lines. Activation of Ron by its ligand, hepatocyte growth factor-like protein (HGFL) was associated with partial rescue from tamoxifen-induced growth inhibition in Ron-expressing cell lines. Western analysis revealed that treatment of the T47D human breast cancer cell line with tamoxifen and HGFL was associated with increased phosphorylation of mitogen-activated protein kinase (MAPK) 1/2 and phosphorylation of serine residue 118 of ER. Expression of ER-dependent genes was increased in cells treated with tamoxifen and HGFL by quantitative reverse transcription-polymerase chain reaction. All of these effects were inhibited by treatment with either a Ron-neutralizing antibody or a MEK1 inhibitor, suggesting the specificity of the effect to Ron, and the involvement of the MAPK 1/2 signaling pathway. In summary, these results illustrate a novel connection between the Ron receptor tyrosine kinase and an important mechanism of tamoxifen resistance in breast cancer. PMID:20689759

McClaine, Rebecca J; Marshall, Aaron M; Wagh, Purnima K; Waltz, Susan E

2010-01-01

99

A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone  

PubMed Central

ABSTRACT The skeleton is a preferred homing site for breast cancer metastasis. To date, treatment options for patients with bone metastases are mostly palliative and the disease is still incurable. Indeed, key mechanisms involved in breast cancer osteotropism are still only partially understood due to the lack of suitable animal models to mimic metastasis of human tumor cells to a human bone microenvironment. In the presented study, we investigate the use of a human tissue-engineered bone construct to develop a humanized xenograft model of breast cancer-induced bone metastasis in a murine host. Primary human osteoblastic cell-seeded melt electrospun scaffolds in combination with recombinant human bone morphogenetic protein 7 were implanted subcutaneously in non-obese diabetic/severe combined immunodeficient mice. The tissue-engineered constructs led to the formation of a morphologically intact ‘organ’ bone incorporating a high amount of mineralized tissue, live osteocytes and bone marrow spaces. The newly formed bone was largely humanized, as indicated by the incorporation of human bone cells and human-derived matrix proteins. After intracardiac injection, the dissemination of luciferase-expressing human breast cancer cell lines to the humanized bone ossicles was detected by bioluminescent imaging. Histological analysis revealed the presence of metastases with clear osteolysis in the newly formed bone. Thus, human tissue-engineered bone constructs can be applied efficiently as a target tissue for human breast cancer cells injected into the blood circulation and replicate the osteolytic phenotype associated with breast cancer-induced bone lesions. In conclusion, we have developed an appropriate model for investigation of species-specific mechanisms of human breast cancer-related bone metastasis in vivo. PMID:24713276

Thibaudeau, Laure; Taubenberger, Anna V.; Holzapfel, Boris M.; Quent, Verena M.; Fuehrmann, Tobias; Hesami, Parisa; Brown, Toby D.; Dalton, Paul D.; Power, Carl A.; Hollier, Brett G.; Hutmacher, Dietmar W.

2014-01-01

100

Ultrastructural characterization and biochemical profile of human gross cystic breast disease  

Microsoft Academic Search

Human gross cystic breast disease is a benign condition affecting about 7–10% of adult women occurring with the highest incidence in the premenopausal decade. Although breast cysts do not represent a preneoplastic condition per se, several studies indicate an increased breast cancer risk in women affected by this pathology. In this report we study 115 breast cystic fluid samples obtained

Manuela Malatesta; Ferdinando Mannello; Maurizio Sebastiani; Antonella Cardinali; Francesco Marcheggiani; Giancarlo Gazzanelli

1998-01-01

101

Molecular characterization of human breast tumor vascular cells.  

PubMed

A detailed understanding of the assortment of genes that are expressed in breast tumor vessels is needed to facilitate the development of novel, molecularly targeted anti-angiogenic agents for breast cancer therapies. Rapid immunohistochemistry using factor VIII-related antibodies was performed on sections of frozen human luminal-A breast tumors (n = 5) and normal breast (n = 5), followed by laser capture microdissection of vascular cells. RNA was extracted and amplified, and fluorescently labeled cDNA was synthesized and hybridized to 44,000-element long-oligonucleotide DNA microarrays. Statistical analysis of microarray was used to compare differences in gene expression between tumor and normal vascular cells, and Expression Analysis Systematic Explorer was used to determine enrichment of gene ontology categories. Protein expression of select genes was confirmed using immunohistochemistry. Of the 1176 genes that were differentially expressed between tumor and normal vascular cells, 55 had a greater than fourfold increase in expression level. The extracellular matrix gene ontology category was increased while the ribosome gene ontology category was decreased. Fibroblast activation protein, secreted frizzled-related protein 2, Janus kinase 3, and neutral sphingomyelinase 2 proteins localized to breast tumor endothelium as assessed by immunohistochemistry, showing significantly greater staining compared with normal tissue. These tumor endothelial marker proteins also exhibited increased expression in breast tumor vessels compared with that in normal tissues. Therefore, these genetic markers may serve as potential targets for the development of angiogenesis inhibitors. PMID:18403594

Bhati, Rajendra; Patterson, Cam; Livasy, Chad A; Fan, Cheng; Ketelsen, David; Hu, Zhiyuan; Reynolds, Evangeline; Tanner, Catherine; Moore, Dominic T; Gabrielli, Franco; Perou, Charles M; Klauber-DeMore, Nancy

2008-05-01

102

Imaging the redox states of human breast cancer core biopsies.  

PubMed

Currently, the gold standard to establish benign vs. malignant breast tissue diagnosis requires an invasive biopsy followed by tissue fixation for subsequent histopathological examination. This process takes at least 24 h resulting in tissues that are less suitable for molecular, functional, or metabolic analysis. We have recently conducted redox scanning (cryogenic NADH/flavoprotein fluorescence imaging) on snap-frozen breast tissue biopsy samples obtained from human breast cancer patients at the time of their breast cancer surgery. The redox state was readily determined by the redox scanner at liquid nitrogen temperature with extraordinary sensitivity, giving oxidized flavoproteins (Fp) an up to tenfold discrimination of cancer to non-cancer of breast in our preliminary data. Our finding suggests that the identified metabolic parameters could discriminate between cancer and non-cancer breast tissues without subjecting tissues to fixatives. The remainder of the frozen tissue is available for additional analysis such as molecular analysis and conventional histopathology. We propose that this novel redox scanning procedure may assist in tissue diagnosis in ex vivo tissues. PMID:22879054

Xu, H N; Tchou, J; Chance, B; Li, L Z

2013-01-01

103

Characterization of an In Vitro Human Breast Epithelial Organoid System.  

National Technical Information Service (NTIS)

We have characterized organoids formed by two types of normal human breast epithelial cells (HBEC) on Matrigel. The results show that mammary gland- like structures can be formed in one day after inoculation of right number and ratio of Type I and Type II...

C. Chang

1998-01-01

104

Molecular Mechanisms of Metastasis Suppression in Human Breast Cancer.  

National Technical Information Service (NTIS)

The major cause of cancer deaths can be attributed to metastasis. Our goal was to identify metastasis-controlling genes for human breast cancer. This research is based upon our finding that microcell-mediated transfer of chromosome 11 into MDA-MB-435 resu...

D. R. Welch

1999-01-01

105

Systems consequences of amplicon formation in human breast cancer.  

PubMed

Chromosomal structural variations play an important role in determining the transcriptional landscape of human breast cancers. To assess the nature of these structural variations, we analyzed eight breast tumor samples with a focus on regions of gene amplification using mate-pair sequencing of long-insert genomic DNA with matched transcriptome profiling. We found that tandem duplications appear to be early events in tumor evolution, especially in the genesis of amplicons. In a detailed reconstruction of events on chromosome 17, we found large unpaired inversions and deletions connect a tandemly duplicated ERBB2 with neighboring 17q21.3 amplicons while simultaneously deleting the intervening BRCA1 tumor suppressor locus. This series of events appeared to be unusually common when examined in larger genomic data sets of breast cancers albeit using approaches with lesser resolution. Using siRNAs in breast cancer cell lines, we showed that the 17q21.3 amplicon harbored a significant number of weak oncogenes that appeared consistently coamplified in primary tumors. Down-regulation of BRCA1 expression augmented the cell proliferation in ERBB2-transfected human normal mammary epithelial cells. Coamplification of other functionally tested oncogenic elements in other breast tumors examined, such as RIPK2 and MYC on chromosome 8, also parallel these findings. Our analyses suggest that structural variations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously and that such oncogenic cassettes are favored during the evolution of a cancer. PMID:25186909

Inaki, Koichiro; Menghi, Francesca; Woo, Xing Yi; Wagner, Joel P; Jacques, Pierre-Étienne; Lee, Yi Fang; Shreckengast, Phung Trang; Soon, Wendy WeiJia; Malhotra, Ankit; Teo, Audrey S M; Hillmer, Axel M; Khng, Alexis Jiaying; Ruan, Xiaoan; Ong, Swee Hoe; Bertrand, Denis; Nagarajan, Niranjan; Karuturi, R Krishna Murthy; Hidalgo Miranda, Alfredo; Liu, Edison T

2014-10-01

106

Systems consequences of amplicon formation in human breast cancer  

PubMed Central

Chromosomal structural variations play an important role in determining the transcriptional landscape of human breast cancers. To assess the nature of these structural variations, we analyzed eight breast tumor samples with a focus on regions of gene amplification using mate-pair sequencing of long-insert genomic DNA with matched transcriptome profiling. We found that tandem duplications appear to be early events in tumor evolution, especially in the genesis of amplicons. In a detailed reconstruction of events on chromosome 17, we found large unpaired inversions and deletions connect a tandemly duplicated ERBB2 with neighboring 17q21.3 amplicons while simultaneously deleting the intervening BRCA1 tumor suppressor locus. This series of events appeared to be unusually common when examined in larger genomic data sets of breast cancers albeit using approaches with lesser resolution. Using siRNAs in breast cancer cell lines, we showed that the 17q21.3 amplicon harbored a significant number of weak oncogenes that appeared consistently coamplified in primary tumors. Down-regulation of BRCA1 expression augmented the cell proliferation in ERBB2-transfected human normal mammary epithelial cells. Coamplification of other functionally tested oncogenic elements in other breast tumors examined, such as RIPK2 and MYC on chromosome 8, also parallel these findings. Our analyses suggest that structural variations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously and that such oncogenic cassettes are favored during the evolution of a cancer. PMID:25186909

Inaki, Koichiro; Menghi, Francesca; Woo, Xing Yi; Wagner, Joel P.; Jacques, Pierre-Etienne; Lee, Yi Fang; Shreckengast, Phung Trang; Soon, Wendy WeiJia; Malhotra, Ankit; Teo, Audrey S.M.; Hillmer, Axel M.; Khng, Alexis Jiaying; Ruan, Xiaoan; Ong, Swee Hoe; Bertrand, Denis; Nagarajan, Niranjan; Karuturi, R. Krishna Murthy; Hidalgo Miranda, Alfredo

2014-01-01

107

Concentration of endogenous estrogens and estrogen metabolites in the NCI-60 human tumor cell lines  

PubMed Central

Background Endogenous estrogens and estrogen metabolites play an important role in the pathogenesis and development of human breast, endometrial, and ovarian cancers. Increasing evidence also supports their involvement in the development of certain lung, colon and prostate cancers. Methods In this study we systemically surveyed endogenous estrogen and estrogen metabolite levels in each of the NCI-60 human tumor cell lines, which include human breast, central nerve system, colon, ovarian, prostate, kidney and non-small cell lung cancers, as well as melanomas and leukemia. The absolute abundances of these metabolites were measured using a liquid chromatography-tandem mass spectrometry method that has been previously utilized for biological fluids such as serum and urine. Results Endogenous estrogens and estrogen metabolites were found in all NCI-60 human tumor cell lines and some were substantially elevated and exceeded the levels found in well known estrogen-dependent and estrogen receptor-positive tumor cells such as MCF-7 and T-47D. While estrogens were expected to be present at high levels in cell lines representing the female reproductive system (that is, breast and ovarian), other cell lines, such as leukemia and colon, also contained very high levels of these steroid hormones. The leukemia cell line RMPI-8226 contained the highest levels of estrone (182.06 pg/106 cells) and 17?-estradiol (753.45 pg/106 cells). In comparison, the ovarian cancer cell line with the highest levels of these estrogens contained only 19.79 and 139.32 pg/106 cells of estrone and 17?-estradiol, respectively. The highest levels of estrone and 17?-estradiol in breast cancer cell lines were only 8.45 and 87.37 pg/106 cells in BT-549 and T-47D cells, respectively. Conclusions The data provided evidence for the presence of significant amounts of endogenous estrogens and estrogen metabolites in cell lines not commonly associated with these steroid hormones. This broad discovery of endogenous estrogens and estrogen metabolites in these cell lines suggest that several human tumors may be beneficially treated using endocrine therapy aimed at estrogen biosynthesis and estrogen-related signaling pathways. PMID:22546321

2012-01-01

108

The Consensus Coding Sequences of Human Breast and Colorectal Cancers  

Microsoft Academic Search

The elucidation of the human genome sequence has made it possible to identify genetic alterations in cancers in unprecedented detail. To begin a systematic analysis of such alterations, we determined the sequence of well-annotated human protein-coding genes in two common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average

Tobias Sjöblom; Siân Jones; Laura D. Wood; D. Williams Parsons; Jimmy Lin; Thomas D. Barber; Diana Mandelker; Rebecca J. Leary; Janine Ptak; Natalie Silliman; Steve Szabo; Phillip Buckhaults; Christopher Farrell; Paul Meeh; Sanford D. Markowitz; Joseph Willis; Dawn Dawson; James K. V. Willson; Adi F. Gazdar; James Hartigan; Leo Wu; Changsheng Liu; Giovanni Parmigiani; Ben Ho Park; Kurtis E. Bachman; Nickolas Papadopoulos; Bert Vogelstein; Kenneth W. Kinzler; Victor E. Velculescu

2006-01-01

109

Novel selective estrogen mimics for the treatment of tamoxifen-resistant breast cancer.  

PubMed

Endocrine-resistant breast cancer is a major clinical obstacle. The use of 17?-estradiol (E2) has reemerged as a potential treatment option following exhaustive use of tamoxifen or aromatase inhibitors, although side effects have hindered its clinical usage. Protein kinase C alpha (PKC?) expression was shown to be a predictor of disease outcome for patients receiving endocrine therapy and may predict a positive response to an estrogenic treatment. Here, we have investigated the use of novel benzothiophene selective estrogen mimics (SEM) as an alternative to E2 for the treatment of tamoxifen-resistant breast cancer. Following in vitro characterization of SEMs, a panel of clinically relevant PKC?-expressing, tamoxifen-resistant models were used to investigate the antitumor effects of these compounds. SEM treatment resulted in growth inhibition and apoptosis of tamoxifen-resistant cell lines in vitro. In vivo SEM treatment induced tumor regression of tamoxifen-resistant T47D:A18/PKC? and T47D:A18-TAM1 tumor models. T47D:A18/PKC? tumor regression was accompanied by translocation of estrogen receptor (ER) ? to extranuclear sites, possibly defining a mechanism through which these SEMs initiate tumor regression. SEM treatment did not stimulate growth of E2-dependent T47D:A18/neo tumors. In addition, unlike E2 or tamoxifen, treatment with SEMs did not stimulate uterine weight gain. These findings suggest the further development of SEMs as a feasible therapeutic strategy for the treatment of endocrine-resistant breast cancer without the side effects associated with E2. Mol Cancer Ther; 13(11); 2515-26. ©2014 AACR. PMID:25205655

Molloy, Mary Ellen; White, Bethany E Perez; Gherezghiher, Teshome; Michalsen, Bradley T; Xiong, Rui; Patel, Hitisha; Zhao, Huiping; Maximov, Philipp Y; Jordan, V Craig; Thatcher, Gregory R J; Tonetti, Debra A

2014-11-01

110

Ocular input for human melatonin regulation: relevance to breast cancer  

NASA Technical Reports Server (NTRS)

The impact of breast cancer on women across the world has been extensive and severe. As prevalence of breast cancer is greatest in industrialized regions, exposure to light at night has been proposed as a potential risk factor. This theory is supported by the epidemiological observations of decreased breast cancer in blind women and increased breast cancer in women who do shift-work. In addition, human, animal and in vitro studies which have investigated the melatonin-cancer dynamic indicate an apparent relationship between light, melatonin and cancer, albeit complex. Recent developments in understanding melatonin regulation by light in humans are examined, with particular attention to factors that contribute to the sensitivity of the light-induced melatonin suppression response. Specifically, the role of spectral characteristics of light is addressed, and recent relevant action spectrum studies in humans and other mammalian species are discussed. Across five action spectra for circadian and other non-visual responses, a peak sensitivity between 446-484 nm was identified. Under highly controlled exposure circumstances, less than 1 lux of monochromatic light elicited a significant suppression of nocturnal melatonin. In view of the possible link between light exposure, melatonin suppression and cancer risk, it is important to continue to identify the basic related ocular physiology. Visual performance, rather than circadian function, has been the primary focus of architectural lighting systems. It is now necessary to reevaluate lighting strategies, with consideration of circadian influences, in an effort to maximize physiological homeostasis and health.

Glickman, Gena; Levin, Robert; Brainard, George C.

2002-01-01

111

An early history of human breast cancer: West meets East  

PubMed Central

Cancer has been increasingly recognized as a global issue. This is especially true in countries like China, where cancer incidence has increased likely because of changes in environment and lifestyle. However, cancer is not a modern disease; early cases have been recorded in ancient medical books in the West and in China. Here, we provide a brief history of cancer, focusing on cancer of the breast, and review the etymology of ai, the Chinese character for cancer. Notable findings from both Western and Chinese traditional medicine are presented to give an overview of the most important, early contributors to our evolving understanding of human breast cancer. We also discuss the earliest historical documents to record patients with breast cancer. PMID:23958056

Yan, Shou-He

2013-01-01

112

Overexpression of sorcin in multidrug-resistant human breast cancer  

PubMed Central

Sorcin is a soluble resistance-related calcium-binding protein, which is expressed in normal mammalian tissues, such as the liver, lungs and heart. It has been observed to be elevated in a number of cancer types, including colorectal, gastric and breast cancer. Its upregulation is usually associated with the development of chemotherapeutic drug resistance. The aim of this study was to evaluate the sorcin expression levels in human serum samples of breast cancer subjects at various stages, and subsequently compare the outcome of neoadjuvant chemotherapy when the sorcin levels fluctuated. In total, 50 subjects were recruited from patients who were admitted to Yantai Yuhunagding Hospital (Yantai, China) and diagnosed with breast cancer. Blood samples prior to and following chemotherapy were assessed using two-dimensional gel electrophoresis (2-DE) and western blot analysis. The 2-DE analysis of the serum samples revealed that sorcin was upregulated in six out of 29 neoadjuvant chemotherapy (NAC)-sensitive patients and, in those who developed multidrug resistance, sorcin was upregulated in 15 out of 21 patients (P<0.01). The differential expression levels of sorcin were confirmed by western blot and immunohistochemical analysis. In conclusion, sorcin expression in the human serum of breast cancer patients who are resistant to NAC was elevated when compared with that of NAC-sensitive patients. PMID:25364401

GONG, ZHAOHUA; SUN, PING; CHU, HONGJIN; ZHU, HUA; SUN, DENGJUN; CHEN, JIAN

2014-01-01

113

Expression and function of tight junction associated molecules in human breast tumor cells is not affected by the Ras-MEK1 pathway.  

PubMed

Constitutive activation of Ras or Ras-mediated signaling pathways is one of the initial steps during tumorigenesis that promotes neoplastic transformation. Recently it was reported that in Ha-Ras overexpressing MDCK cells the tight junction proteins claudin-1, occludin and ZO-1 were absent at cell-cell contact sites but present in the cytoplasm. Inhibition of MEK1 activity recruited all three proteins to the cell membrane leading to a restoration of the tight junction barrier function in MDCK cells. In order to evaluate the relevance of the MEK1 pathway in tight junction regulation in breast cancer cells, we investigated the effect ofMEK1 inhibition on expression of claudin-1, occludin and ZO-1 in natively claudin-1 expressing T47-D cells (low Ras activity), claudin-1 negative MCF-7 cells (elevated Ras activity) as well as two retroviral claudin-1 transduced MCF-7 daughter cell lines with prominent membrane and cytoplasmic claudin-1 dominant homing, respectively. Although we effectively blocked phosphorylation of MAPKs ERK-1 and ERK-2 using the selective MEK1 inhibitor PD98059, no quantitative changes of mRNA or protein levels of claudin-1, occludin and ZO-1 could be detected in all cell lines investigated. Furthermore, immnfluorescence analysis of claudin-1 revealed that inhibition of the MAPK pathway did not alter th e subcellular cytoplasmic distribution of claudin-1 to be more membrane specific. Finally, the diffusion barrier properties of tight junctions as analyzed by transepithelial resistance (TER) or paracellular flux analysis of 3 and 40 kDa dextran of tight junctions were not altered in the claudin-1 positive T47-D and the MCF-7 cell lines. Our findings indicate that the proposed involvement of the Ras-MEK-ERK pathway is likely not involved in the dysregulated tight junction formation in breast tumor cells and indicates that elevated activity of Ras might not be of general importance for the disruption of tight junction structures in breast tumors. PMID:12839332

Macek, R; Swisshelm, K; Kubbies, M

2003-02-01

114

Modelling defined mixtures of environmental oestrogens found in domestic animal and sewage treatment effluents using an in vitro oestrogen-mediated transcriptional activation assay (T47D-KBluc  

EPA Science Inventory

There is growing concern that exposure of fish, wildlife, and humans to water sources contaminated with estrogens could potentially impact reproductive health. Environmental estrogens can come from various sources including concentrated animal feedlot operations (CAFO), municipal...

115

Fluopsin C induces oncosis of human breast adenocarcinoma cells  

PubMed Central

Aim: Fluopsin C, an antibiotic isolated from Pseudomonas jinanesis, has shown antitumor effects on several cancer cell lines. In the current study, the oncotic cell death induced by fluopsin C was investigated in human breast adenocarcinoma cells in vitro. Methods: Human breast adenocarcinoma cell lines MCF-7 and MD-MBA-231 were used. The cytotoxicity was evaluated using MTT assay. Time-lapse microscopy and transmission electron microscopy were used to observe the morphological changes. Cell membrane integrity was assessed with propidium iodide (PI) uptake and lactate dehydrogenase (LDH) assay. Flow cytometry was used to measure reactive oxygen species (ROS) level and mitochondrial membrane potential (??m). A multimode microplate reader was used to analyze the intracellular ATP level. The changes in cytoskeletal system were investigated with Western blotting and immunostaining. Results: Fluopsin C (0.5-8 ?mol/L) reduced the cell viability in dose- and time-dependent manners. Its IC50 values in MCF-7 and MD-MBA-231 cells at 24 h were 0.9 and 1.03 ?mol/L, respectively. Fluopsin C (2 ?mol/L) induced oncosis in both the breast adenocarcinoma cells characterized by membrane blebbing and swelling, which was blocked by pretreatment with the pan-caspase inhibitor Z-VAD-fmk. In MCF-7 cells, fluopsin C caused PI uptake into the cells, significantly increased LDH release, induced cytoskeletal system degradation and ROS accumulation, decreased the intracellular ATP level and ??m. Noticeably, fluopsin C exerted comparable cytotoxicity against the normal human hepatocytes (HL7702) and human mammary epithelial cells with the IC50 values at 24 h of 2.7 and 2.4 ?mol/L, respectively. Conclusion: Oncotic cell death was involved in the anticancer effects of fluopsin C on human breast adenocarcinoma cells in vitro. The hepatoxicity of fluopsin C should not be ignored. PMID:23708552

Ma, Li-sha; Jiang, Chang-you; Cui, Min; Lu, Rong; Liu, Shan-shan; Zheng, Bei-bei; Li, Lin; Li, Xia

2013-01-01

116

Anticomplement activities of human breast-milk  

Microsoft Academic Search

Objective and Design: It has long been observed that the human milk possesses significant anti-inflammatory properties, while simultaneously protecting the infant against many intestinal and respiratory pathogens. There is, however, a paucity of information on the degree and extent of this anti-inflammatory activity. In the present study, the inhibitory effects of different fractions of human milk on serum complement activity

M. O. Ogundele

1999-01-01

117

GPER mediates estrogen-induced signaling and proliferation in human breast epithelial cells and normal and malignant breast.  

PubMed

17?-Estradiol (estrogen), through receptor binding and activation, is required for mammary gland development. Estrogen stimulates epithelial proliferation in the mammary gland, promoting ductal elongation and morphogenesis. In addition to a developmental role, estrogen promotes proliferation in tumorigenic settings, particularly breast cancer. The proliferative effects of estrogen in the normal breast and breast tumors are attributed to estrogen receptor ?. Although in vitro studies have demonstrated that the G protein-coupled estrogen receptor (GPER, previously called GPR30) can modulate proliferation in breast cancer cells both positively and negatively depending on cellular context, its role in proliferation in the intact normal or malignant breast remains unclear. Estrogen-induced GPER-dependent proliferation was assessed in the immortalized nontumorigenic human breast epithelial cell line, MCF10A, and an ex vivo organ culture model employing human breast tissue from reduction mammoplasty or tumor resections. Stimulation by estrogen and the GPER-selective agonist G-1 increased the mitotic index in MCF10A cells and proportion of cells in the cell cycle in human breast and breast cancer explants, suggesting increased proliferation. Inhibition of candidate signaling pathways that may link GPER activation to proliferation revealed a dependence on Src, epidermal growth factor receptor transactivation by heparin-bound EGF and subsequent ERK phosphorylation. Proliferation was not dependent on matrix metalloproteinase cleavage of membrane-bound pro-HB-EGF. The contribution of GPER to estrogen-induced proliferation in MCF10A cells and breast tissue was confirmed by the ability of GPER-selective antagonist G36 to abrogate estrogen- and G-1-induced proliferation, and the ability of siRNA knockdown of GPER to reduce estrogen- and G-1-induced proliferation in MCF10A cells. This is the first study to demonstrate GPER-dependent proliferation in primary normal and malignant human tissue, revealing a role for GPER in estrogen-induced breast physiology and pathology. PMID:24718936

Scaling, Allison L; Prossnitz, Eric R; Hathaway, Helen J

2014-06-01

118

Cytotoxicity of fucosterol containing fraction of marine algae against breast and colon carcinoma cell line  

PubMed Central

Context: Marine algae produce different secondary metabolites with a wide range of biological activities. Many studies have been achieved on the screening of biological effects of marine organisms and a lot of active compounds were isolated and characterized. Aims: In an attempt to find cytotoxic compound of hexane fraction, isolation, identification, and cytotoxicity of active compound of this fraction were performed. Materials and Methods: In this study, total methanolic (70%) extract and partition fractions of hexane, chloroform (CHCl3), ethyl acetate (EtOAc), and MeOH–H2O of Sargassum angustifolium, Chondria dasyphylla, and Ulva flexuosa, collected from coastlines of the Persian Gulf in south of Iran, were studied against colon carcinoma (HT-29), colorectal adenocarcinoma (Caco-2), breast ductal carcinoma (T47D), and Swiss mouse embryo fibroblast (NIH 3T3) cell lines by MTT assay. Statistical Analysis Used: IC50 (median growth inhibitory concentration) values were calculated by Sigmaplot (10) software. Results: Hexane fraction of Chondria dasyphylla (IC50 82.26 ± 4.09 ?g/ml) and MeOH-H2O fraction of Ulva flexuosa (IC50 116.92 ± 8.58 ?g/ml) showed cytotoxic activity against proliferation of T47D cells. Hexane fraction of Sargassum angustifolium was also observed for cytotoxicity against T47D and HT-29 cell lines (IC50 166.42 ± 26.7 and 190.24 ± 52.8 ?g/ml), respectively. An investigation of a component from the hexane fraction of Sargassum angustifolium yielded a steroidal metabolite, fucosterol, with cytotoxicity in T47D and HT29 (IC50 27.94 ± 9.3 and 70.41 ± 7.5 ?g/ml). Conclusions: These results indicated that fucosterol, the most abundant phytosterol in brown algae, is responsible for cytotoxic effect of this extract against breast and colon carcinoma cell lines. PMID:22438665

Khanavi, Mahnaz; Gheidarloo, Razieh; Sadati, Nargess; Ardekani, Mohammad Reza Shams; Nabavi, Seyed Mohammad Bagher; Tavajohi, Shohreh; Ostad, Seyed Nasser

2012-01-01

119

Augmented Release of Matrix Metalloproteinase-9 by PKC Activation in Organotypic Cultures of Human Breast Cancer and Adjacent Normal Breast Tissue and Fibroadenoma  

Microsoft Academic Search

The organotypic culture technique and quantitative gelatin zymography were used to determine the expression of matrix metalloproteinase (MMP)-9 and MMP-2 in human breast cancer and adjacent normal breast tissue and fibroadenoma. MMP-9 and MMP2 were constitutively expressed in all cultures. The release of these two enzymes in breast cancer was higher than that in adjacent normal breast tissue and fibroadenoma.

Trang-Tiau Wu; Jen-Hsiang Tsai; Ju-Hsin Tsai; Shou-Jen Kuo; Shi-Yau Yu; Chih-Yang Huang; Hai-Yung Hsieh; Yih-Shou Hsieh; Jer-Yuh Liu

120

FT-Raman spectroscopy study of human breast tissue  

NASA Astrophysics Data System (ADS)

Optical spectroscopy has been extensively studied as a potential in vivo diagnostic tool to provide information about the chemical and morphologic structure of tissue. Raman Spectroscpy is an inelastic scattering process that can provide a wealth of spectral features that can be related to the specific molecular structure of the sample. This article reports results of an in vitro study of the FT-Raman human breast tissue spectra. An Nd:YAG laser at 1064nm was used as the excitation source in the FT-Raman Spectrometer. The neoplastic human breast samples, both Fibroadenoma and ICD, were obtained during therapeutical routine medical procedures required by the primary disease, and the non-diseased human tissue was obtained in plastic surgery. No sample preparation was needed for the FT-Raman spectra collection. The FT-Raman spectra were recorded from normal, benign (Fibroadenomas) and malignant (IDC-Intraductal Carcinoma) samples, adding up 51 different areas. The main spectral differences of a typical FT-Raman spectra of a Normal (Non-diseased), Fibroadenoma, and Infiltrating Ductal Carcinoma (IDC) breast tissue at the interval of 600 to 1800cm-1, which may differentiate diagnostically the sample, were found in the bands of 1230 to 1295cm-1, 1440 to 1460 cm-1 and 1650 to 1680 cm-1, assigned to the vibrational bands of the carbohydrate-amide III, proteins and lipids, and carbohydrate-amide I, respectively.

Bitar Carter, Renata A.; Martin, Airton A.; Netto, Mario M.; Soares, Fernando A.

2004-07-01

121

Human Breast Milk and Xenoestrogen Exposure: A Possible Impact on Human Health  

Microsoft Academic Search

Human milk is the best natural and optimal food for neonates with several immunologic, developmental and practical advantages throughout childhood. Although the World Health Organization strongly supports breastfeeding, it recognizes the potential health risks posed by the presence of environmental toxicants in breast milk. Contamination of human milk is widespread and due to decades of inadequately controlled pollution by toxicants,

Francesco Massart; Joshua Chuck Harrell; Giovanni Federico; Giuseppe Saggese

2005-01-01

122

Analyzing the regulation of metabolic pathways in human breast cancer  

PubMed Central

Background Tumor therapy mainly attacks the metabolism to interfere the tumor's anabolism and signaling of proliferative second messengers. However, the metabolic demands of different cancers are very heterogeneous and depend on their origin of tissue, age, gender and other clinical parameters. We investigated tumor specific regulation in the metabolism of breast cancer. Methods For this, we mapped gene expression data from microarrays onto the corresponding enzymes and their metabolic reaction network. We used Haar Wavelet transforms on optimally arranged grid representations of metabolic pathways as a pattern recognition method to detect orchestrated regulation of neighboring enzymes in the network. Significant combined expression patterns were used to select metabolic pathways showing shifted regulation of the aggressive tumors. Results Besides up-regulation for energy production and nucleotide anabolism, we found an interesting cellular switch in the interplay of biosynthesis of steroids and bile acids. The biosynthesis of steroids was up-regulated for estrogen synthesis which is needed for proliferative signaling in breast cancer. In turn, the decomposition of steroid precursors was blocked by down-regulation of the bile acid pathway. Conclusion We applied an intelligent pattern recognition method for analyzing the regulation of metabolism and elucidated substantial regulation of human breast cancer at the interplay of cholesterol biosynthesis and bile acid metabolism pointing to specific breast cancer treatment. PMID:20831783

2010-01-01

123

Brefeldin A Reduces Anchorage-Independent Survival, Cancer Stem Cell Potential and Migration of MDA-MB-231 Human Breast Cancer Cells.  

PubMed

Cancer stem cells (CSCs) are a subset of cancer cells in tumors or established cancer cell lines that can initiate and sustain the growth of tumors in vivo. Cancer stem cells can be enriched in serum-free, suspended cultures that allow the formation of tumorspheres over several days to weeks. Brefeldin A (BFA) is a mycotoxin that induces endoplasmic reticulum (ER) stress in eukaryotic cells. We found that BFA, at sub-microgram per milliliter concentrations, preferentially induced cell death in MDA-MB-231 suspension cultures (EC50: 0.016 µg/mL) compared to adhesion cultures. BFA also effectively inhibited clonogenic activity and the migration and matrix metalloproteinases-9 (MMP-9) activity of MDA-MB-231 cells. Western blotting analysis indicated that the effects of BFA may be mediated by the down-regulation of breast CSC marker CD44 and anti-apoptotic proteins Bcl-2 and Mcl-1, as well as the reversal of epithelial-mesenchymal transition. Furthermore, BFA also displayed selective cytotoxicity toward suspended MDA-MB-468 cells, and suppressed tumorsphere formation in T47D and MDA-MB-453 cells, suggesting that BFA may be effective against breast cancer cells of various phenotypes. PMID:25356567

Tseng, Chao-Neng; Hong, Yi-Ren; Chang, Hsueh-Wei; Yu, Tsai-Jung; Hung, Ting-Wei; Hou, Ming-Feng; Yuan, Shyng-Shiou F; Cho, Chung-Lung; Liu, Chien-Tsung; Chiu, Chien-Chih; Huang, Chih-Jen

2014-01-01

124

Breast tumor specific mutation in GATA3 affects physiological mechanisms regulating transcription factor turnover  

PubMed Central

Background The transcription factor GATA3 is a favorable prognostic indicator in estrogen receptor-? (ER?)-positive breast tumors in which it participates with ER? and FOXA1 in a complex transcriptional regulatory program driving tumor growth. GATA3 mutations are frequent in breast cancer and have been classified as driver mutations. To elucidate the contribution(s) of GATA3 alterations to cancer, we studied two breast cancer cell lines, MCF7, which carries a heterozygous frameshift mutation in the second zinc finger of GATA3, and T47D, wild-type at this locus. Methods Immunofluorescence staining and subcellular fractionation were employed to verify cellular localization of GATA3 in T47D and MCF7 cells. To test protein stability, cells were treated with translation inhibitor, cycloheximide or proteasome inhibitor, MG132, and GATA3 abundance was measured over time using immunoblot. GATA3 turn-over in response to hormone was determined by treating the cells with estradiol or ER? agonist, ICI 182,780. DNA binding ability of recombinant GATA3 was evaluated using electrophoretic mobility shift assay and heparin chromatography. Genomic location of GATA3 in MCF7 and T47D cells was assessed by chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq). Results GATA3 localized in the nucleus in T47D and MCF7 cells, regardless of the mutation status. The truncated protein in MCF7 had impaired interaction with chromatin and was easily released from the nucleus. Recombinant mutant GATA3 was able to bind DNA to a lesser degree than the wild-type protein. Heterozygosity for the truncating mutation conferred protection from regulated turnover of GATA3, ER? and FOXA1 following estrogen stimulation in MCF7 cells. Thus, mutant GATA3 uncoupled protein-level regulation of master regulatory transcription factors from hormone action. Consistent with increased protein stability, ChIP-seq profiling identified greater genome-wide accumulation of GATA3 in MCF7 cells bearing the mutation, albeit with a similar distribution across the genome, comparing to T47D cells. Conclusions We propose that this specific, cancer-derived mutation in GATA3 deregulates physiologic protein turnover, stabilizes GATA3 binding across the genome and modulates the response of breast cancer cells to estrogen signaling. PMID:24758297

2014-01-01

125

Paclitaxel Combined with Inhibitors of Glucose and Hydroperoxide Metabolism Enhances Breast Cancer Cell Killing Via H2O2-Mediated Oxidative Stress  

PubMed Central

Cancer cells (relative to normal cells) demonstrate alterations in oxidative metabolism characterized by increased steady-state levels of reactive oxygen species [i.e. hydrogen peroxide, H2O2] that may be compensated for by increased glucose metabolism but the therapeutic significance of these observations is unknown. In the current study, inhibitors of glucose [i.e., 2-deoxy-D-glucose, 2DG] and hydroperoxide [i.e., L-buthionine-S, R-sulfoximine, BSO] metabolism were utilized in combination with a chemotherapeutic agent paclitaxel [PTX], thought to induce oxidative stress, to treat breast cancer cells. 2DG+PTX were found to be more toxic than either agent alone in T47D and MDA-MB231 human breast cancer cells, but not in normal human fibroblasts or normal human mammary epithelial cells. Increases in parameters indicative of oxidative stress, including steady-state levels of H2O2, total glutathione, and glutathione disulfide accompanied the enhanced toxicity of 2DG+PTX in cancer cells. Antioxidants, including N-acetyl-cysteine [NAC], polyethylene glycol-conjugated catalase [PEG-CAT] and superoxide dismutase [PEG-SOD], inhibited the toxicity of 2DG+PTX and suppressed parameters indicative of oxidative stress in cancer cells, while inhibition of glutathione synthesis using BSO further sensitized breast cancer cells to 2DG+PTX. These results show that combining inhibitors of glucose [2DG] and hydroperoxide [BSO] metabolism with PTX selectively (relative to normal cells) enhances breast cancer cell killing via H2O2-induced metabolic oxidative stress, and suggests that this biochemical rationale may be effectively utilized to treat breast cancers. PMID:20083194

Hadzic, Tanja; Aykin-Burns, Nukhet; Zhu, Yueming; Coleman, Mitchell C.; Leick, Katie; Jacobson, Geraldine M.; Spitz, Douglas R.

2010-01-01

126

Influence of age and parity on the development of the human breast  

Microsoft Academic Search

Breast cancer is heavily influenced by the reproductive history of the individual. Pregnancy has a protective effect which is attributed to differences in the degree of differentiation of the breast. The purpose of this work was to determine whether the quantity and the type of parenchymal structures present in the human breast were related to the age and parity history

J. Russo; R. Rivera; I. H. Russo

1992-01-01

127

Variations in amplification and expression of the ornithine decarboxylase gene in human breast cancer cells  

Microsoft Academic Search

The polyamine biosynthetic pathway plays a critical role in the growth of human breast cancer cells. Ornithine decarboxylase (ODC) is a key enzyme in polyamine biosynthesis. To understand the regulation of ODC activity and polyamine accumulation in breast cancer cells, we studied amplification and expression of the ODC gene in four breast cancer cell lines. ODC gene dosage was analyzed

Thresia Thomas; David T. Kiang; Olli A. Jfinne; T. J. Thomas

1991-01-01

128

Cell Type and Culture ConditionDependent Alternative Splicing in Human Breast Cancer Cells Revealed by  

E-print Network

lead to predisposition to breast cancer and ovarian cancer (2, 3). A G-to-T transversion mutation of breast and ovarian cancer within a family (4). This mutation leads to the skipping of exon 18 in the BRCACell Type and Culture Condition­Dependent Alternative Splicing in Human Breast Cancer Cells

Ares Jr., Manny

129

A comparative study of canine and human breast cancer.  

PubMed

The incidence of mammary tumours in the bitch is probably three times as great as in women. While many of these tumours are mixed mammary tumours about one-third are carcinomas which resemble human breast carcinomas. Allowing for differences in life span, the age at onset is similar in both species. The World Health Organization classification of tumours and dysplasias of the canine mammary gland follows as far as possible the WHO classification for human breast tumours. Clinical staging of canine mammary tumours has now been completed. Some prognostic factors are similar in both species but regional lymph node metastasis does not seem to be of major importance in the bitch; mitotic activity may also not be as important as in women. Metastatic spread is broadly similar in both species except that involvement of the liver and skeleton is not as common in the bitch as in women. In older normal Beagles hyperplastic and neoplastic nodules commonly appear in the mammary gland, and they occur earlier in animals receiving large doses of progestogens. This has produced problems for the drug industry when conducting long-term carcinogenicity tests on progestogens present in the human contraceptive pill. Despite considerable endocrinological differences between the two species, oophorectomy is sparing for breast cancer in both. As in women, oestrogen and progesterone receptors have been detected in mammary carcinomas in bitches. Canine tumours can be grown in tissue culture but cloned cell lines have not yet been obtained. Transplantation can be made into nude mice and immunosuppressed neonatal dogs. The prognosis following mastectomy for invasive tubular adenocarcinoma and invasive solid carcinoma in the bitch is poor and these histological types make the best models for breast cancer in women. International trials are planned using chemotherapy and/or immunotherapy following mastectomy and, as results can be obtained within 3 years of commencement, it is expected that canine mammary tumours will play an increasingly important role in research which may lead to improved methods of treatment in human breast cancer. PMID:396282

Owen, L N

1979-01-01

130

Quantification of prostate-specific antigen immunoreactivity in human breast cyst fluids  

Microsoft Academic Search

Summary The frequency of gross cystic breast disease in premenopausal women and its possible association with in-creased breast cancer risk emphasises the importance of investigations relating to breast cyst fluid composition. In order to contribute to a better analysis of this medium, we have measured the presence of prostate-specific antigen immuno-reactivity in sixty-four human breast cyst fluids. Data analyses show

Ferdinando Mannello; GianDomenico Bocchiotti; Giuseppe Bianchi; Francesco Marcheggiani; Giancarlo Gazzanelli

1996-01-01

131

Jadomycins are cytotoxic to ABCB1-, ABCC1-, and ABCG2-overexpressing MCF7 breast cancer cells.  

PubMed

Multidrug resistance remains a major obstacle in the effective treatment of metastatic breast cancer. One mechanism by which multidrug resistance is conferred is the decreased intracellular drug accumulation due to the upregulation of the ATP-binding cassette (ABC) transporters. We have previously demonstrated that jadomycins, polyketide-derived natural products produced by Streptomyces venezuelae ISP5230, inhibit the growth of the human breast ductal carcinoma cell lines T47D and MDA-MB-435. To expand our understanding of jadomycin pharmacology, the goal of the present study was to determine whether the function of ABC efflux transporters affects the anticancer activity of jadomycins to MCF7 breast cancer cells. Seven jadomycin analogs (DNV, B, L, SPhG, F, S, and T) effectively reduced the viability of MCF7 control and ABCB1-, ABCC1-, or ABCG2-overexpressing drug-resistant MCF7 breast cancer cells as measured by methyltetrazolium cell viability assays and lactate dehydrogenase cytotoxicity assays. The inhibition of ABCB1, ABCC1, or ABCG2 with verapamil, MK-571, or Ko-143, respectively, did not augment the cytotoxicity of jadomycins DNV, B, L, SPhG, F, S, or T in drug-resistant MCF7 cells. Furthermore, jadomycins B, L, SPhG, F, S, and T did not increase the intracellular accumulation of ABCB1, ABCC1, or ABCG2 fluorescent substrates in HEK-293 cells stably transfected with ABCB1, ABCC1, or ABCG2. We conclude that jadomycins B, L, SPhG, F, S, and T are effective agents in the eradication of MCF7 breast cancer cells grown in culture, and that their cytotoxicities are minimally affected by ABCB1, ABCC1, and ABCG2 efflux transporter function. PMID:24231527

Issa, Mark E; Hall, Steven R; Dupuis, Stephanie N; Graham, Cathy L; Jakeman, David L; Goralski, Kerry B

2014-03-01

132

Persistent organic pollutants in human breast milk from Asian countries.  

PubMed

In this paper, we concisely reviewed the contamination of persistent organic pollutants (POPs) such as polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), biphenyls (PCBs), dichlorodiphenyltrichloroethane and its metabolites (DDTs), hexachlorocyclohexane isomers (HCHs), chlordane compounds (CHLs), hexachlorobenzene (HCB) in human breast milk collected from Asian countries such as Japan, China, Philippines, Vietnam, Cambodia, India, Malaysia, and Indonesia during 1999-2003. Dioxins, PCBs, CHLs in Japanese, and DDTs in Vietnamese, Chinese, Cambodian, Malaysian, and HCHs in Chinese, Indian, and HCB in Chinese breast milk were predominant. In India, levels of dioxins and related compounds (DRCs) in the mothers living around the open dumping site were notably higher than those from the reference site and other Asian developing countries, indicating that significant pollution sources of DRCs are present in the dumping site of India and the residents there have been exposed to relatively higher levels of these contaminants possibly via bovine milk. PMID:16949712

Tanabe, Shinsuke; Kunisue, Tatsuya

2007-03-01

133

Gene expression profiles of human breast cancer progression  

PubMed Central

Although distinct pathological stages of breast cancer have been described, the molecular differences among these stages are largely unknown. Here, through the combined use of laser capture microdissection and DNA microarrays, we have generated in situ gene expression profiles of the premalignant, preinvasive, and invasive stages of human breast cancer. Our data reveal extensive similarities at the transcriptome level among the distinct stages of progression and suggest that gene expression alterations conferring the potential for invasive growth are already present in the preinvasive stages. In contrast to tumor stage, different tumor grades are associated with distinct gene expression signatures. Furthermore, a subset of genes associated with high tumor grade is quantitatively correlated with the transition from preinvasive to invasive growth. PMID:12714683

Ma, Xiao-Jun; Salunga, Ranelle; Tuggle, J. Todd; Gaudet, Justin; Enright, Edward; McQuary, Philip; Payette, Terry; Pistone, Maria; Stecker, Kimberly; Zhang, Brian M.; Zhou, Yi-Xiong; Varnholt, Heike; Smith, Barbara; Gadd, Michelle; Chatfield, Erica; Kessler, Jessica; Baer, Thomas M.; Erlander, Mark G.; Sgroi, Dennis C.

2003-01-01

134

The over-expression of ERbeta modifies estradiol effects on mitochondrial dynamics in breast cancer cell line.  

PubMed

Mitochondrial biogenesis and function are under the control of 17?-estradiol, which acts through two distinct estrogen receptors (alpha or beta), and the estrogen receptors ratio can determine the final effect of 17?-estradiol on mitochondria. Our aim was to study the effects of 17?-estradiol on mitochondrial biogenesis, dynamics and function in breast cancer cell lines with different estrogen receptors ratios. Mitochondrial biogenesis was increased in MDA-MB-231 (with only estrogen receptor beta expression), T47D (normal estrogen receptors ratio) and MCF-7 (highest estrogen receptors ratio) breast cancer cell lines, in response to different mitochondrial and cellular status. In fact, mitochondria of the MDA-MB-231 and T47D cell lines maintained their functionality, although, the MCF-7 cell line did suffer an important decrease in mitochondrial function. Thus, mitochondrial biogenesis increased in MCF-7 with the aim of mitigating these defective mitochondria. In normal conditions, mitophagic processes remove defective mitochondria to refresh the mitochondrial pool. Mitochondrial dynamics were also under control by 17?-estradiol, and showed modifications in the fusion/fission processes and the modulation of mitochondrial removal. In fact, cells with only estrogen receptor beta or with a low estrogen receptors ratio, such as MDA-MB-231 and T47D, showed an increase in fusion processes. However, the MCF-7 cell line, with more estrogen receptor alpha, also showed an increase in fusion processes, even though the fission processes were diminished and led to an accumulation of unfunctional mitochondria. Finally, the importance of estrogen receptor beta in mitochondrial biogenesis, function, as well as in mitochondrial dynamics was examined. Using the T47D-estrogen receptor beta tetracycline-inducible cell line, the results confirmed that when the overexpression of estrogen receptor beta was inhibited, there was an increase in mitochondrial biogenesis, although these mitochondria were less functional, and with fewer fission events, although there was an increase in fusion processes. PMID:23618876

Sastre-Serra, Jorge; Nadal-Serrano, Mercedes; Pons, Daniel Gabriel; Roca, Pilar; Oliver, Jordi

2013-07-01

135

Marker evaluation of human breast and bladder cancers  

SciTech Connect

We are investigating multiple markers in human breast and bladder cancers. Our aim is to identify markers that are clinically relevant and that contribute to our understanding of the disease process in individual patients. Good markers accurately assess the malignant potential of a cancer in an individual patient. Thus, they help identify those cancers that will recur, and they may be used to predict more accurately time to recurrence, response to treatment, and overall prognosis. Therapy and patient management may then be optimized to the individual patient. Relevant markers reflect the underlying pathobiology of individual tumors. As a tissue undergoes transformation from benign to malignant, the cells lose their differentiated phenotype. As a generalization, the more the cellular phenotype, cellular proliferation and cellular genotype depart from normal, the more advanced is the tumor in its biological evolution and the more likely it is that the patient has a poor prognosis. We use three studies to illustrate our investigation of potential tumor markers. Breast cancers are labeled in vivo with 5-bromodeoxyuridine (BrdUrd) to give a direct measure of the tumor labeling index. Bladder cancers are analyzed immunocytochemically using an antibody against proliferation. Finally, the techniques of molecular genetics are used to detect allelic loss in breast cancers. 6 refs., 3 figs.

Mayall, B.H.; Carroll, P.R.; Chen, Ling-Chun; Cohen, M.B.; Goodson, W.H. III; Smith, H.S.; Waldman, F.M. (California Univ., San Francisco, CA (USA))

1990-11-02

136

Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells.  

PubMed

Cyclin E2, but not cyclin E1, is included in several gene signatures that predict disease progression in either tamoxifen-resistant or metastatic breast cancer. We therefore examined the role of cyclin E2 in antiestrogen resistance in vitro and its potential for therapeutic targeting through cyclin-dependent kinase (CDK) inhibition. High expression of CCNE2, but not CCNE1, was characteristic of the luminal B and HER2 subtypes of breast cancer and was strongly predictive of shorter distant metastasis-free survival following endocrine therapy. After antiestrogen treatment of MCF-7 breast cancer cells, cyclin E2 mRNA and protein were downregulated and cyclin E2-CDK2 activity decreased. However, this regulation was lost in tamoxifen-resistant (MCF-7 TAMR) cells, which overexpressed cyclin E2. Expression of either cyclin E1 or E2 in T-47D breast cancer cells conferred acute antiestrogen resistance, suggesting that cyclin E overexpression contributes to the antiestrogen resistance of tamoxifen-resistant cells. Ectopic expression of cyclin E1 or E2 also reduced sensitivity to CDK4, but not CDK2, inhibition. Proliferation of tamoxifen-resistant cells was inhibited by RNAi-mediated knockdown of cyclin E1, cyclin E2, or CDK2. Furthermore, CDK2 inhibition of E-cyclin overexpressing cells and tamoxifen-resistant cells restored sensitivity to tamoxifen or CDK4 inhibition. Cyclin E2 overexpression is therefore a potential mechanism of resistance to both endocrine therapy and CDK4 inhibition. CDK2 inhibitors hold promise as a component of combination therapies in endocrine-resistant disease as they effectively inhibit cyclin E1 and E2 overexpressing cells and enhance the efficacy of other therapeutics. PMID:22564725

Caldon, C Elizabeth; Sergio, C Marcelo; Kang, Jian; Muthukaruppan, Anita; Boersma, Marijke N; Stone, Andrew; Barraclough, Jane; Lee, Christine S; Black, Michael A; Miller, Lance D; Gee, Julia M; Nicholson, Rob I; Sutherland, Robert L; Print, Cristin G; Musgrove, Elizabeth A

2012-07-01

137

The Relevance of Mouse Models to Understanding the Development and Progression of Human Breast Cancer  

Microsoft Academic Search

Mouse modeling of human breast cancer has developed tremendously over the past ten years. Human breast cancer is characterized\\u000a by enormous biological diversity and, collectively, the new models have come much closer to encompassing this diversity. They\\u000a have provided a deeper understanding of the fundamental events that mediate the initiation, development, and progression of\\u000a breast cancer, and they offer new

D. Craig Allred; Daniel Medina

2008-01-01

138

Distinctive Gene Expression Patterns in Human Mammary Epithelial Cells and Breast Cancers  

Microsoft Academic Search

cDNA microarrays and a clustering algorithm were used to identify patterns of gene expression in human mammary epithelial cells growing in culture and in primary human breast tumors. Clusters of coexpressed genes identified through manipulations of mammary epithelial cells in vitro also showed consistent patterns of variation in expression among breast tumor samples. By using immunohistochemistry with antibodies against proteins

Charles M. Perou; Stefanie S. Jeffrey; Matt van de Rijn; Christian A. Rees; Michael B. Eisen; Douglas T. Ross; Alexander Pergamenschikov; Cheryl F. Williams; Shirley X. Zhu; Jeffrey C. F. Lee; Deval Lashkari; Dari Shalon; Patrick O. Brown; David Botstein

1999-01-01

139

Human mammaglobin in breast cancer: a brief review of its clinical utility  

PubMed Central

Human mammaglobin is a member of the uteroglobin proteins family that has recently been tested as a specific marker for breast cancer. While low levels may be seen in normal breast tissue, expression is increased dramatically in breast cancer and is correlated with higher grade. Detection in blood and body fluids is also correlated with cancer metastasis, and its levels with prognosis. This promises to be a useful screen for early detection of breast cancer, especially in high risk individuals. Mammoglobin has also been used for immunotherapeutic targeting of breast cancer cells. However, there are some controversies regarding its diagnostic efficacy and prognostic value, which warrant further study. PMID:25027076

Al Joudi, Fawwaz Shakir

2014-01-01

140

The role of annexin A1 in expression of matrix metalloproteinase-9 and invasion of breast cancer cells  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer We evaluated the effect of ANXA1 on promoting migration and invasion in MDA-MB-231 cells. Black-Right-Pointing-Pointer ANXA1 siRNA inhibits invasion and migration. Black-Right-Pointing-Pointer ANXA1 regulates MMP-9 expression and activity. Black-Right-Pointing-Pointer ANX-1 siRNA inhibits the activation of NF-{kappa}B in MDA-MB-231 cells. -- Abstract: Matrix metalloproteinase-9 (MMP-9) plays an important role in the invasion and metastasis of cancer cells. However, the regulatory mechanism of MMP-9 expression and its biological effects on breast cancer development remain obscure. In the current study, we examined the potential role of annexin A1 (ANXA1) in regulating migration and invasion in breast cancer cell lines. Both ANXA1 mRNA and protein are expressed in the highly invasive, hormone-insensitive human breast cancer cell lines MDA-MB-231 and SKBr3, but not in the hormone-responsive cell lines MCF-7 and T47D. Downregulation of ANXA1 expression with specific small interfering RNAs (ANXA1 siRNA) in MDA-MB-231 cells resulted in decreased cancer cell migration and invasion. Ablation of ANXA1 expression decreases the expression of MMP-9 at both the mRNA and protein levels and also reduces the proteolytic activity of MMP-9 in MDA-MB-231 cells. Moreover, silencing ANXA1 also decreases the transcriptional activity of MMP-9 by the suppression of nuclear factor kappa-B (NF-{kappa}B) activity. Collectively, these results indicate that ANXA1 functions as a positive regulator of MMP-9 expression and invasion of breast cancer cells through specific activation of the NF-{kappa}B signaling pathway.

Kang, Hyereen [Department of Medicine, Graduate School, University of Ulsan, Pungnap-2 dong, Songpa-gu, Seoul (Korea, Republic of)] [Department of Medicine, Graduate School, University of Ulsan, Pungnap-2 dong, Songpa-gu, Seoul (Korea, Republic of); Ko, Jesang [School of Life Sciences and Biotechnology, Korea University, Seoul 136-701 (Korea, Republic of)] [School of Life Sciences and Biotechnology, Korea University, Seoul 136-701 (Korea, Republic of); Jang, Sung-Wuk, E-mail: swjang@amc.seoul.kr [Department of Medicine, Graduate School, University of Ulsan, Pungnap-2 dong, Songpa-gu, Seoul (Korea, Republic of)] [Department of Medicine, Graduate School, University of Ulsan, Pungnap-2 dong, Songpa-gu, Seoul (Korea, Republic of)

2012-06-22

141

Estrogen receptor expression and sensitivity to paclitaxel in breast cancer.  

PubMed

A retrospective analysis of CALGB trial 9344 suggested paclitaxel administration following cyclophosphamide and doxorubicin adjuvant chemotherapy is most beneficial for patients with ERalpha negative (ERalpha-) breast cancer. Since the cytotoxic effects of paclitaxel are cell cycle dependent, we postulated that the relationship between ERalpha and the effectiveness of adjuvant paclitaxel reflects the observation that ERalpha positive (ERalpha+) breast cancers proliferate more slowly than ERalpha- breast cancers. Three in vitro models (MCF-7, T47D and ZR-75) were examined to compare growth rates and paclitaxel-induced apoptosis in ERalpha+ and ERalpha- clones of the same, originally ERalpha+ cell line. For the T47D and ZR-75 cell lines, loss of ERalpha was associated with a decrease in doubling time and an increase in paclitaxel sensitivity. However, when cell culture conditions were altered to achieve equivalent cell proliferation rates, no difference in paclitaxel sensitivity was observed. Similarly, an ERalpha- clone of MCF-7 cells that did not exhibit an enhanced growth rate compared to its ERalpha+ counterpart also did not show increased paclitaxel sensitivity. The combined apoptotic effects of tamoxifen and paclitaxel on MCF-7 cells were not synergistic or even clearly additive. In these in vitro models, the effectiveness of paclitaxel correlated more closely with growth rate than ERalpha expression. These data suggest that measurements of tumor proliferation may provide more accurate predictive markers for the benefits of adjuvant paclitaxel than ERalpha analysis. PMID:15020841

Dougherty, Michele K; Schumaker, Lisa M; Jordan, V Craig; Welshons, Wade V; Curran, Edward M; Ellis, Matthew J; El-Ashry, Dorraya

2004-05-01

142

Expression of keratinocyte growth factor and its receptor in human breast cancer.  

PubMed Central

The level of expression of keratinocyte growth factor (KGF) mRNA has been measured in human breast cell lines, purified populations of epithelial cells, myoepithelial cells and fibroblasts from reduction mammoplasty tissue and a panel of 42 breast cancers and 30 non-malignant human breast tissues using a semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) procedure. We found similar levels of KGF mRNA in malignant and non-malignant breast tissues. The study of the amount of KGF mRNA in breast cell lines and purified populations of cells revealed that fibroblasts are the predominant source of KGF with malignant and non-malignant epithelial cells containing very low levels of KGF mRNA. We have examined the distribution of fibroblast growth factor receptor (FGFR)-2-IIIb, which is a high-affinity receptor for KGF and find that it is present on malignant and non-malignant epithelial cells. The level of FGFR-2-IIIb present on breast cancer cell lines was sufficient for KGF stimulation of breast cancer cell proliferation. Other members of the fibroblast growth factor family have been either not expressed in the human breast (FGF3, FGF4) or have been found at much reduced levels in breast cancer (FGF1, FGF2) and this is the first member of the family to potentially influence the progression of breast cancer through stimulation of cell division. Images Figure 1 Figure 3 Figure 4 PMID:9184170

Bansal, G. S.; Cox, H. C.; Marsh, S.; Gomm, J. J.; Yiangou, C.; Luqmani, Y.; Coombes, R. C.; Johnston, C. L.

1997-01-01

143

IMP3 expression is associated with epithelial-mesenchymal transition in breast cancer  

PubMed Central

IMP3 plays an important role in tumor invasion and metastasis, to which epithelial to mesenchymal transition (EMT) also contributes. The purpose of this study was to investigate whether IMP3 can regulate invasion and metastasis through EMT in breast cancers. The protein expression levels of IMP3 and EMT markers were analyzed by immunohistochemistry in 180 paraffin-embedded human breast tissue samples. There was an inverse correlation of IMP3 with E-cadherin protein expression (P = 0.042). IMP3 expression directly correlated with both Slug (P = 0.004) and vimentin (P < 0.001). Changes in E-cadherin, vimentin, and Slug mRNA and protein levels were examined by quantitative real-time reverse polymerase chain reaction (qRT-PCR) and western blotting. Overexpression of IMP3 reduced the expression of E-cadherin and upregulated Slug and vimentin in transfected cells. In contrast, knocking down IMP3 had the opposite expression of the three proteins. Ribo-immunoprecipitation qPCR revealed that IMP3 binds Slug mRNA directly. In a transwell assay, overexpression of Slug rescued the cell migration and invasion caused by silencing IMP3 in MDA-MB-231 cells. On the other hand, knockdown of Slug in T47D-IMP3 cells could also have the opposite change. Our results strengthen the association of IMP3 with the regulation of EMT. Slug is a functional target of IMP3. IMP3 could therefore promote invasion and migration through the EMT in breast cancer cells. PMID:25031719

Su, Peng; Hu, Jing; Zhang, Hui; Li, Weiwei; Jia, Ming; Zhang, Xiaofang; Wu, Xiaojuan; Cheng, Hongxia; Xiang, Lei; Zhou, Gengyin

2014-01-01

144

Crosstalk between the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and the vitamin D receptor (VDR) in human breast cancer cells: PPAR{gamma} binds to VDR and inhibits 1{alpha},25-dihydroxyvitamin D{sub 3} mediated transactivation  

SciTech Connect

Heterodimerization and cross-talk between nuclear hormone receptors often occurs. For example, estrogen receptor alpha (ER{alpha}) physically binds to peroxisome proliferator-activated receptor gamma (PPAR{gamma}) and inhibits its transcriptional activity. The interaction between PPAR{gamma} and the vitamin D receptor (VDR) however, is unknown. Here, we elucidate the molecular mechanisms linking PPAR{gamma} and VDR signaling, and for the first time we show that PPAR{gamma} physically associates with VDR in human breast cancer cells. We found that overexpression of PPAR{gamma} decreased 1{alpha},25-dihydroxyvitamin D{sub 3} (1,25D{sub 3}) mediated transcriptional activity of the vitamin D target gene, CYP24A1, by 49% and the activity of VDRE-luc, a vitamin D responsive reporter, by 75% in T47D human breast cancer cells. Deletion mutation experiments illustrated that helices 1 and 4 of PPAR{gamma}'s hinge and ligand binding domains, respectively, governed this suppressive function. Additionally, abrogation of PPAR{gamma}'s AF2 domain attenuated its repressive action on 1,25D{sub 3} transactivation, indicating that this domain is integral in inhibiting VDR signaling. PPAR{gamma} was also found to compete with VDR for their binding partner retinoid X receptor alpha (RXR{alpha}). Overexpression of RXR{alpha} blocked PPAR{gamma}'s suppressive effect on 1,25D{sub 3} action, enhancing VDR signaling. In conclusion, these observations uncover molecular mechanisms connecting the PPAR{gamma} and VDR pathways. -- Highlights: PPAR{gamma}'s role on 1{alpha},25-dihydroxyvitamin D{sub 3} transcriptional activity is examined. Black-Right-Pointing-Pointer PPAR{gamma} physically binds to VDR and inhibits 1{alpha},25-dihydroxyvitamin D{sub 3} action. Black-Right-Pointing-Pointer PPAR{gamma}'s hinge and ligand binding domains are important for this inhibitory effect. Black-Right-Pointing-Pointer PPAR{gamma} competes with VDR for the availability of their binding partner, RXR{alpha}.

Alimirah, Fatouma; Peng, Xinjian; Yuan, Liang; Mehta, Rajeshwari R. [Cancer Biology Division, IIT Research Institute, 10 West 35th Street, Chicago, IL 60616 (United States)] [Cancer Biology Division, IIT Research Institute, 10 West 35th Street, Chicago, IL 60616 (United States); Knethen, Andreas von [Institute of Biochemistry, Johann Wolfgang Goethe University, Frankfurt (Germany)] [Institute of Biochemistry, Johann Wolfgang Goethe University, Frankfurt (Germany); Choubey, Divaker [Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, P.O. Box 670056, Cincinnati, OH 45267 (United States)] [Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, P.O. Box 670056, Cincinnati, OH 45267 (United States); Mehta, Rajendra G., E-mail: rmehta@iitri.org [Cancer Biology Division, IIT Research Institute, 10 West 35th Street, Chicago, IL 60616 (United States)

2012-11-15

145

Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells.  

PubMed

Genetic and environmental factors can modulate the level of sensitivity to various hormones, including estrogens. Enhanced sensitivity to estradiol (E2) has been demonstrated in several biological conditions, such as in sheep during the nonbreeding season, in untreated patients with Turner's syndrome, and in the prepubertal state in normal girls. We postulated that secondary responses to hormonal therapy in patients with breast cancer could also result from enhanced E2 sensitivity, developing as an adaptive mechanism to E2 deprivation. The present study used the MCF-7 human breast cancer cell line as a model system to test the concept that enhanced sensitivity to E2 may occur as a result of adaptation to low E2 levels. After depriving MCF-7 cells of estrogens in tissue culture medium for periods of 1-6 months, we established conditions under which replication could be stimulated maximally by 10(-14)-10(-15) mol/L E2. In contrast, wild-type cells not exposed to estrogen deprivation required 10(-10) mol/L E2 to grow at the same rate. Further, the concentration of the antiestrogen, ICI 164384, needed to inhibit growth by 50% in estrogen-deprived cells was much lower than that required in wild-type cells (i.e. 10(-15) vs. 10(-9) mol/L). Nude mice implanted with these estrogen-deprived cells demonstrated an earlier appearance of palpable tumors in response to E2 than animals bearing wild-type cells. Reexposure to 10(-10)-10(-9) mol/L E2, either in vivo or in vitro, returned these cells to the level of estrogen sensitivity observed in wild-type cells. Taken together, these observations suggest that breast cancer cells can adapt to low levels of estrogens by enhancing their sensitivity to E2. PMID:7559875

Masamura, S; Santner, S J; Heitjan, D F; Santen, R J

1995-10-01

146

Radiosensitization effects of berberine on human breast cancer cells.  

PubMed

Berberine, an isoquinoline derivative alkaloid, has recently been shown to have antitumor activity. The present study aimed to investigate the effects of the concomitant administration of berberine and radiation on breast cancer. The effects of berberine on the radiosensitivity of MCF-7 and MDA-MB-468 cells were evaluated by using cell clonogenic assays. Cells pre-treated with berberine or dimethyl sulfoxide (DMSO) for 24 h were irradiated using a Faxitron Cabinet X-ray System to deliver the indicated doses (0, 1, 2, 3 and 4 Gy). Changes in cell cycle distribution were determined by flow cytometry. ?-H2AX foci were detected by immunofluorescence staining. The levels of Ku70, Ku86 and RAD51 proteins were evaluated by western blot analysis. We observed that berberine increased the MCF-7 and MDA-MB-468 cell radiosensitivity with cell clonogenic assays. the radiation-induced G2/M cell cycle delay was reduced in the MCF-7 cells pre-teated with berberine. Berberine pre-treatment prolonged the persistence of DNA double-strand breaks in the MCF-7 cell line. In comparison with the control cells, the protein levels of RAD51 were decreased in the MCF-7 and MDA-MB-468 cells treated with berberine, and in the cells pre-treated with 15 µM berberine for 24 h, the level of RAD51 protein decreased significantly at the indicated time-points (0, 2, 6 and 24 h) following X-ray exposure. In conclusion, berberine sensitizes human breast cancer cells to ionizing radiation by inducing cell cycle arrest and the downregulation of the homologous recombination repair protein, RAD51. Berberine may be a promising radiosensitizer for the treatment of breast cancer. PMID:22895634

Wang, Jing; Liu, Qiao; Yang, Qifeng

2012-11-01

147

Sodwanone and Yardenone Triterpenes from a South African Species of the Marine Sponge Axinella Inhibit Hypoxia-Inducible Factor-1 (HIF-1) Activation in both Breast and Prostate Tumor Cells  

PubMed Central

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that promotes tumor cell adaptation and survival under hypoxic conditions. HIF-1 is currently recognized as an important molecular target for anti-cancer drug discovery. A T47D breast tumor cell-based reporter assay was used to evaluate the NCI Open Repository of marine invertebrates and algae lipid extracts for HIF-1 inhibitory activity. Bioassay-guided fractionation and isolation of an active extract from Axinella sp. yielded seven new sodwanone triterpenoids [3-epi-sodwanone K (1), 3-epi-sodwanone K 3-acetate (2), 10,11-dihydrosodwanone B (4), sodwanones T–W (3, 7, 8, 9), the new yardenone triterpene 12R-hydroxyyardenone (10), and the previously reported compounds sodwanone A (5), sodwanone B (6), and yardenone (11). The structures and relative configurations of these Axinella metabolites were determined spectroscopically. The absolute configuration of 1 was determined by the modified Mosher ester procedure. Sodwanone V (8) inhibited both hypoxia-induced and iron chelator (1,10-phenanthroline)-induced HIF-1 activation in T47D breast tumor cells (IC50 15 ?M) and 8 was the only sodwanone that inhibited HIF-1 activation in PC-3 prostate tumor cells (IC50 15 ?M). Compounds 1, 3, 4, and 5 inhibited hypoxia-induced HIF-1 activation in T47D cells (IC50 values 20-25 ?M). Compound 2 was cytotoxic to T47D cells (IC50 22 ?M) and 8 showed cytotoxicity to MDA-MB-231 breast tumor cells (IC50 23 ?M). PMID:17190448

Dai, Jingqiu; Fishback, James A.; Zhou, Yu-Dong; Nagle, Dale G.

2010-01-01

148

Sodwanone and yardenone triterpenes from a South African species of the marine sponge Axinella inhibit hypoxia-inducible factor-1 (HIF-1) activation in both breast and prostate tumor cells.  

PubMed

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that promotes tumor cell adaptation and survival under hypoxic conditions. HIF-1 is currently recognized as an important molecular target for anticancer drug discovery. A T47D breast tumor cell-based reporter assay was used to evaluate the NCI Open Repository of marine invertebrates and algae lipid extracts for HIF-1 inhibitory activity. Bioassay-guided fractionation and isolation of an active extract from Axinella sp. yielded seven new sodwanone triterpenoids [3-epi-sodwanone K (1), 3-epi-sodwanone K 3-acetate (2), 10,11-dihydrosodwanone B (4), sodwanones T-W (3, 7, 8, 9)], the new yardenone triterpene 12R-hydroxyyardenone (10), and the previously reported compounds sodwanone A (5), sodwanone B (6), and yardenone (11). The structures and relative configurations of these Axinella metabolites were determined spectroscopically. The absolute configuration of 1 was determined by the modified Mosher ester procedure. Sodwanone V (8) inhibited both hypoxia-induced and iron chelator (1,10-phenanthroline)-induced HIF-1 activation in T47D breast tumor cells (IC50 15 microM), and 8 was the only sodwanone that inhibited HIF-1 activation in PC-3 prostate tumor cells (IC50 15 microM). Compounds 1, 3, 4, and 5 inhibited hypoxia-induced HIF-1 activation in T47D cells (IC50 values 20-25 microM). Compound 2 was cytotoxic to T47D cells (IC50 22 microM), and 8 showed cytotoxicity to MDA-MB-231 breast tumor cells (IC50 23 microM). PMID:17190448

Dai, Jingqiu; Fishback, James A; Zhou, Yu-Dong; Nagle, Dale G

2006-12-01

149

A novel antiestrogen agent Shikonin inhibits estrogen-dependent gene transcription in human breast cancer cells  

Microsoft Academic Search

Shikonin (SK) has been isolated and identified as a key bioactive component in an herbal plant, Shikon (gromwell). In this\\u000a study, we investigated antiestrogen activity of SK in breast cancer cells. In human breast cancer cells, we observed that\\u000a treatment with SK inhibits tumor cell growth in estrogen receptor ? (ER?)-positive, but not ER?-negative breast cancer cells.\\u000a Estrogen-dependent cell growth

Yuan Yao; Qun Zhou

2010-01-01

150

Protein Profiling of Human Breast Tumor Cells Identifies Novel Biomarkers Associated with Molecular Subtypes  

Microsoft Academic Search

Molecular subtypes of breast cancer with relevant bio- logical and clinical features have been defined recently, notably ERBB2-overexpressing, basal-like, and luminal- like subtypes. To investigate the ability of mass spec- trometry-based proteomics technologies to analyze the molecular complexity of human breast cancer, we per- formed a SELDI-TOF MS-based protein profiling of hu- man breast cell lines (BCLs). Triton-soluble proteins from

Anthony Goncalves; Emmanuelle Charafe-Jauffret; Francois Bertucci; Stephane Audebert; Yves Toiron; Benjamin Esterni; Florence Monville; Carole Tarpin; Jocelyne Jacquemier; Gilles Houvenaeghel; Christian Chabannon; Jean-Marc Extra; Patrice Viens; Jean-Paul Borg; D. Birnbaum

2008-01-01

151

Fulvestrant radiosensitizes human estrogen receptor-positive breast cancer cells  

SciTech Connect

Highlights: ? Fulvestrant radiosensitizes MCF-7 cells. ? Fulvestrant increases G1 arrest and decreases S phase in MCF-7 cells. ? Fulvestrant down-regulates DNA-PKcs and RAD51 in MCF-7 cells. -- Abstract: The optimal sequencing for hormonal therapy and radiation are yet to be determined. We utilized fulvestrant, which is showing promise as an alternative to other agents in the clinical setting of hormonal therapy, to assess the cellular effects of concomitant anti-estrogen therapy (fulvestrant) with radiation (F + RT). This study was conducted to assess the effects of fulvestrant alone vs. F + RT on hormone-receptor positive breast cancer to determine if any positive or negative combined effects exist. The effects of F + RT on human breast cancer cells were assessed using MCF-7 clonogenic and tetrazolium salt colorimetric (MTT) assays. The assays were irradiated with a dose of 0, 2, 4, 6 Gy ± fulvestrant. The effects of F + RT vs. single adjuvant treatment alone on cell-cycle distribution were assessed using flow cytometry; relative expression of repair proteins (Ku70, Ku80, DNA-PKcs, Rad51) was assessed using Western Blot analysis. Cell growth for radiation alone vs. F + RT was 0.885 ± 0.013 vs. 0.622 ± 0.029 @2 Gy, 0.599 ± 0.045 vs. 0.475 ± 0.054 @4 Gy, and 0.472 ± 0.021 vs. 0.380 ± 0.018 @6 Gy RT (p = 0.003). While irradiation alone induced G2/M cell cycle arrest, the combination of F + RT induced cell redistribution in the G1 phase and produced a significant decrease in the proportion of cells in G2 phase arrest and in the S phase in breast cancer cells (p < 0.01). Furthermore, levels of repair proteins DNA-PKcs and Rad51 were significantly decreased in the cells treated with F + RT compared with irradiation alone. F + RT leads to a decrease in the surviving fraction, increased cell cycle arrest, down regulating of nonhomologous repair protein DNA-PKcs and homologous recombination repair protein RAD51. Thus, our findings suggest that F + RT increases breast cancer cell radiosensitivity compared with radiation alone. These findings have salient implications for designing clinical trials using fulvestrant and radiation therapy.

Wang, Jing, E-mail: wangstella5@163.com [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China) [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China); Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province (China); Yang, Qifeng, E-mail: qifengy@gmail.com [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China)] [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China); Haffty, Bruce G., E-mail: hafftybg@umdnj.edu [Department of Radiation Oncology, UMDNJ-Robert Wood Johnson School of Medicine, Cancer Institute of New Jersey, NB (United States); Li, Xiaoyan, E-mail: xiaoyanli1219@gmail.com [Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province (China)] [Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province (China); Moran, Meena S., E-mail: meena.moran@yale.edu [Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT (United States)

2013-02-08

152

Molecular profiles of progesterone receptor loss in human breast tumors  

PubMed Central

Background Patient prognosis and response to endocrine therapy in breast cancer correlate with protein expression of both estrogen receptor (ER) and progesterone receptor (PR), with poorer outcome in patients with ER+/PR? compared to ER+/PR+ tumors. Methods To better understand the underlying biology of ER+/PR? tumors, we examined RNA expression (n > 1000 tumors) and DNA copy number profiles from five previously published studies of human breast cancers with clinically assigned hormone receptor status (ER+/PR+, ER+/PR?, and ER?/PR?). Results We identified an expression signature of genes with either elevated or diminished RNA levels specifically in ER+/PR+ compared to ER?/PR? and ER+/PR? tumors. We similarly identified a gene signature specific to ER?/PR? tumors. ER+/PR? tumors, on the other hand, were a mixture of three different subtypes: tumors manifesting the ER+/PR+ signature, tumors manifesting the ER?/PR? signature, and tumors not associating with ER+/PR+ or ER?/PR? tumors (which we considered “true” ER+/PR?). In analyses of both tamoxifen-treated and untreated patients, ER+/PR? breast cancers defined by RNA profiling were associated with poor patient outcome, worse than those with pure ER+/PR+ patterns; these differences were not observed when using clinical assays to assign ER and PR status. ER+/PR? tumors also showed twice as many DNA copy number gains or losses compared to ER+/PR+ and ER?PR? tumors. Targets of transcriptional up-regulation by specific oncogenic pathways, including PI3K/Akt/mTOR, were enriched in both ER+/PR? and ER?/PR? compared to ER+/PR+ tumors. Conclusion ER+/PR? tumors as defined by RNA profiling represent a distinct subset of breast cancer with aggressive features and poor outcome, despite being clinically ER+. Multigene assays derived from our gene signatures could conceivably provide an improved clinical assay for inferring PR status for prognostic and therapeutic purposes. PMID:18425577

Creighton, Chad J.; Osborne, C. Kent; van de Vijver, Marc J.; Foekens, John A.; Klijn, Jan; Horlings, Hugo M.; Nuyten, Dimitry; Wang, Yixin; Zhang, Yi; Chamness, Gary C.; Hilsenbeck, Susan G.; Lee, Adrian V.; Schiff, Rachel

2008-01-01

153

Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival  

PubMed Central

Introduction The breast microenvironment can either retard or accelerate the events associated with progression of latent cancers. However, the actions of local physiological mediators in the context of breast cancers are poorly understood. Serotonin (5-HT) is a critical local regulator of epithelial homeostasis in the breast and other organs. Herein, we report complex alterations in the intrinsic mammary gland serotonin system of human breast cancers. Methods Serotonin biosynthetic capacity was analyzed in human breast tumor tissue microarrays using immunohistochemistry for tryptophan hydroxylase 1 (TPH1). Serotonin receptors (5-HT1-7) were analyzed in human breast tumors using the Oncomine database. Serotonin receptor expression, signal transduction, and 5-HT effects on breast cancer cell phenotype were compared in non-transformed and transformed human breast cells. Results In the context of the normal mammary gland, 5-HT acts as a physiological regulator of lactation and involution, in part by favoring growth arrest and cell death. This tightly regulated 5-HT system is subverted in multiple ways in human breast cancers. Specifically, TPH1 expression undergoes a non-linear change during progression, with increased expression during malignant progression. Correspondingly, the tightly regulated pattern of 5-HT receptors becomes dysregulated in human breast cancer cells, resulting in both ectopic expression of some isoforms and suppression of others. The receptor expression change is accompanied by altered downstream signaling of 5-HT receptors in human breast cancer cells, resulting in resistance to 5-HT-induced apoptosis, and stimulated proliferation. Conclusions Our data constitutes the first report of direct involvement of 5-HT in human breast cancer. Increased 5-HT biosynthetic capacity accompanied by multiple changes in 5-HT receptor expression and signaling favor malignant progression of human breast cancer cells (for example, stimulated proliferation, inappropriate cell survival). This occurs through uncoupling of serotonin from the homeostatic regulatory mechanisms of the normal mammary epithelium. The findings open a new avenue for identification of diagnostic and prognostic markers, and valuable new therapeutic targets for managing breast cancer. PMID:19903352

2009-01-01

154

Quality assurance\\/quality control procedures for chlorinated hydrocarbons in human breast adipose tissue  

Microsoft Academic Search

Extensive literature exists supporting the accumulation of organochlorine pesticides such as DDT [2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane], and polychlorinated biphenyls (PCBs) in human adipose tissue. Debate has surfaced concerning the link between these environmental contaminants and human breast cancer. Accurate residue analysis and proper analytical procedures are critical in determining the extent to which these compounds play a role in human breast cancer. Further,

S. Archibeque-Engle; J. D. Tessari; D. T. Winn

1996-01-01

155

Multiplexed ion beam imaging (MIBI) of human breast tumors  

PubMed Central

Immunohistochemistry (IHC) is a tool for visualizing protein expression employed as part of the diagnostic work-up for the majority of solid tissue malignancies. Existing IHC methods use antibodies tagged with fluorophores or enzyme reporters that generate colored pigments. Because these reporters exhibit spectral and spatial overlap when used simultaneously, multiplexed IHC is not routinely used in clinical settings. We have developed a method that uses secondary ion mass spectrometry to image antibodies tagged with isotopically pure elemental metal reporters. Multiplexed ion beam imaging (MIBI) is capable of analyzing up to 100 targets simultaneously over a five-log dynamic range. Here, we used MIBI to analyze formalin-fixed, paraffin-embedded (FFPE) human breast tumor tissue sections stained with ten labels simultaneously. The resulting data suggest that MIBI will provide new insights by integrating tissue microarchitecture with highly multiplexed protein expression patterns, and will be valuable for basic research, drug discovery and clinical diagnostics. PMID:24584119

Angelo, Michael; Bendall, Sean C.; Finck, Rachel; Hale, Matthew B.; Hitzman, Chuck; Borowsky, Alexander D.; Levenson, Richard M.; Lowe, John B.; Liu, Scot D.; Zhao, Shuchun; Natkunam, Yasodha; Nolan, Garry P.

2014-01-01

156

The breast\\/nipple\\/areola complex and human sexuality  

Microsoft Academic Search

The male or female breast\\/nipple\\/areola complex arises from a common mammary stem cell and develops similarly in the foetus and during infancy. At puberty the male's breasts remain rudimentary but the female's develop further, mainly through oestrogen and progesterone stimulation, and become more sensitive. Female breasts serve both nutritive and sexual functions, unlike other primates they develop at puberty before

Roy J. Levin

2006-01-01

157

Breast Cancer  

MedlinePLUS

... for it when they are older. What Is Breast Cancer? The human body is made of tiny building ... liver, or elsewhere. Continue Why Do People Get Breast Cancer? Any woman can get breast cancer, but doctors ...

158

Endocrine Disruptors Fludioxonil and Fenhexamid Stimulate miR-21 Expression in Breast Cancer Cells  

PubMed Central

Fenhexamid and fludioxonil are antifungal agents used in agricultural applications, which are present at measurable amounts in fruits and vegetables. Fenhexamid and fludioxonil showed endocrine disruptor activity as antiandrogens in an androgen receptor reporter assay in engineered human breast cancer cells. Little is known about how environmental chemicals regulate microRNA (miRNA) expression. This study examined the effect of fenhexamid and fludioxonil on the expression of the oncomiR miR-21 in MCF-7, T47D, and MDA-MB-231 human breast cancer cells and downstream targets of miR-21 in MCF-7 cells. Fenhexamid and fludioxonil stimulated miR-21 expression in a concentration-dependent manner and reduced the expression of miR-21 target Pdcd4 protein. Antisense to miR-21 blocked the increase in Pdcd4 protein by fenhexamid and fludioxonil. Fenhexamid and fludioxonil reduced miR-125b and miR-181a, demonstrating specificity of miRNA regulation. Induction of miR-21 was inhibited by the estrogen receptor antagonist fulvestrant, by androgen receptor antagonist bicalutamide, by actinomycin D and cycloheximide, and by inhibitors of the mitogen-activated protein kinases and phosphoinositide 3-kinase pathways. Fenhexamid activation was inhibited by the arylhydrocarbon receptor antagonist ?-napthoflavone. Fenhexamid and fludioxonil did not affect dihydrotestosterone-induced miR-21 expression. Fludioxonil, but not fenhexamid, inhibited MCF-7 cell viability, and both inhibited estradiol-induced cell proliferation and reduced cell motility. Together these data indicate that fenhexamid and fludioxonil use similar and distinct mechanisms to increase miR-21 expression with downstream antiestrogenic activity. PMID:23052036

Teng, Yun; Manavalan, Tissa T.; Klinge, Carolyn M.

2013-01-01

159

Exploring the stem cell and non-stem cell constituents of human breast milk.  

PubMed

The immense potency of nutritional components of human breast milk and importance of breastfeeding is known worldwide. Recent researches had identified stem cells as integral component of human breast milk. Nevertheless, there is little proof of evidence on the stem cell constituents of breast milk. It is imperative to explore the cellular constituents of human breast milk, including of stem cells, to open new avenue in child's development and regeneration. Thus, we aimed at identifying the cellular constituents of human breast milk by phenotypic characterisation of diverse cell surface markers of hematopoietic stem cells (CD 34, CD 133, CD 117), mesenchymal stem cells (CD 90, CD 105, CD 73), myoepithelial cells (CD 29, CD 44), Immune cells (CD 209, CD 86, CD 83, CD 14, CD 13, HLADR, CD 45), as well as cell adhesion molecules (CD 31, CD 54, CD 166, CD 106, CD 49d), and other markers (ABCG2, CD140b) using flowcytometry. We found a lower expression of CD 34 (13.07 ± 2.0 %), CD 90 (7.79 ± 0.8 %) and CD 73 (2.19 ± 0.41 %), indicating scanty hematopoietic and mesenchymal stem cell population in human breast milk. On contrary, myoepithelial progenitors, cell adhesion molecules, immune cells and growth factors were identified as the major constituents of breast milk. Overall, this study illuminates the benefits of breast feeding as breast milk encompasses heterogeneous cellular components that benefits child's growth, immunity and development. However, further research on these constituents of human breast milk will widen their applicability in treatment of neonatal disorders. PMID:22940915

Indumathi, S; Dhanasekaran, M; Rajkumar, J S; Sudarsanam, D

2013-05-01

160

Cadmium Malignantly Transforms Normal Human Breast Epithelial Cells into a Basal-like Phenotype  

PubMed Central

Background Breast cancer has recently been linked to cadmium exposure. Although not uniformly supported, it is hypothesized that cadmium acts as a metalloestrogenic carcinogen via the estrogen receptor (ER). Thus, we studied the effects of chronic exposure to cadmium on the normal human breast epithelial cell line MCF-10A, which is ER-negative but can convert to ER-positive during malignant transformation. Methods Cells were continuously exposed to low-level cadmium (2.5 ?M) and checked in vitro and by xenograft study for signs of malignant transformation. Transformant cells were molecularly characterized by protein and transcript analysis of key genes in breast cancer. Results Over 40 weeks of cadmium exposure, cells showed increasing secretion of matrix metalloproteinase-9, loss of contact inhibition, increased colony formation, and increasing invasion, all typical for cancer cells. Inoculation of cadmium-treated cells into mice produced invasive, metastatic anaplastic carcinoma with myoepithelial components. These cadmium-transformed breast epithelial (CTBE) cells displayed characteristics of basal-like breast carcinoma, including ER-? negativity and HER2 (human epidermal growth factor receptor 2) negativity, reduced expression of BRCA1 (breast cancer susceptibility gene 1), and increased CK5 (cytokeratin 5) and p63 expression. CK5 and p63, both breast stem cell markers, were prominently overexpressed in CTBE cell mounds, indicative of persistent proliferation. CTBE cells showed global DNA hypomethylation and c-myc and k-ras overexpression, typical in aggressive breast cancers. CTBE cell xenograft tumors were also ER-? negative. Conclusions Cadmium malignantly transforms normal human breast epithelial cells—through a mechanism not requiring ER-?—into a basal-like cancer phenotype. Direct cadmium induction of a malignant phenotype in human breast epithelial cells strongly fortifies a potential role in breast cancer. PMID:20049202

Benbrahim-Tallaa, Lamia; Tokar, Erik J.; Diwan, Bhalchandra A.; Dill, Anna L.; Coppin, Jean-Francois; Waalkes, Michael P.

2009-01-01

161

Free ?-human chorionic gonadotropin, total human chorionic gonadotropin and maternal risk of breast cancer  

PubMed Central

Background We investigated whether the free ?-human chorionic gonadotropin (free ?-hCG) would provide additional information to that provided by total hCG alone and thus be useful in future epidemiological studies relating hCG to maternal breast cancer risk. Materials & methods Cases (n = 159) and controls (n = 286) were a subset of our previous study within the Northern Sweden Maternity Cohort on total hCG during primiparous pregnancy and breast cancer risk. Results The associations between total hCG (hazard ratio: 0.79; 95% CI: 0.49–1.27), free ?-hCG (hazard ratio: 0.85; 95% CI: 0.33–2.18) and maternal risk of breast cancer were very similar in all analyses and mutual adjustment for either one had minor effects on the risk estimates. Conclusion In the absence of a reliable assay on intact hCG, total hCG alone can be used in epidemiological studies investigating hCG and breast cancer risk, as free ?-hCG does not appear to provide any additional information. PMID:24559445

Toriola, Adetunji T; Tolockiene, Egle; Schock, Helena; Surcel, Helja-Marja; Zeleniuch-Jacquotte, Anne; Wadell, Goran; Toniolo, Paolo; Lundin, Eva; Grankvist, Kjell; Lukanova, Annekatrin

2014-01-01

162

Frondoside A inhibits human breast cancer cell survival, migration, invasion and the growth of breast tumor xenografts  

Microsoft Academic Search

Breast cancer is a major challenge for pharmacologists to develop new drugs to improve the survival of cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa. It has been demonstrated that Frondoside A inhibited the growth of pancreatic cancer cells in vitro and in vivo. We investigated the impact of Frondoside A on human

Nadia Al Marzouqi; Rabah Iratni; Abderrahim Nemmar; Kholoud Arafat; Mahmood Ahmed Al Sultan; Javed Yasin; Peter Collin; Jan Mester; Thomas E. Adrian; Samir Attoub

2011-01-01

163

Knockdown of ANLN by lentivirus inhibits cell growth and migration in human breast cancer.  

PubMed

Anillin (ANLN), an actin-binding protein, is required for cytokinesis. Recently, ANLN has been identified as a biomarker in diverse human cancers; however, the precise role of ANLN in breast cancer remains unclear. In this study, we firstly detected the expression of ANLN in 71 patients with breast cancer by immunohistochemistry, and found ANLN was highly expressed in breast cancer tissues. To evaluate the function of ANLN in breast cancer cells, we employed lentivirus-mediated RNA interference to knock down ANLN expression in two human breast cancer cell lines, MDA-MB-231, and ZR-75-30. Knockdown of ANLN remarkably inhibited the proliferation rate and colony formation ability of both breast cancer cell lines. Moreover, flow cytometry analysis showed that depletion of ANLN in MDA-MB-231 cells blocked the cell cycle progression, with more cells delayed at G2/M phase, due to phosphorylation of Cdc2 and suppression of Cyclin D1. Furthermore, knockdown of ANLN strongly suppressed the migration of breast cancer cells, strengthening the evidence that ANLN could be involved in breast cancer progression. Our results may suggest ANLN as a potential target candidate in breast cancer. PMID:25223638

Zhou, Weibing; Wang, Zhan; Shen, Ni; Pi, Weiwei; Jiang, Wuzhong; Huang, Juan; Hu, Yuanping; Li, Xiong; Sun, Lunquan

2015-01-01

164

Identification of novel molecular regulators of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in breast cancer cells by RNAi screening  

PubMed Central

Introduction Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to its receptors, TRAIL-receptor 1 (TRAIL-R1) and TRAIL-receptor 2 (TRAIL-R2), leading to apoptosis by activation of caspase-8 and the downstream executioner caspases, caspase-3 and caspase-7 (caspase-3/7). Triple-negative breast cancer (TNBC) cell lines with a mesenchymal phenotype are sensitive to TRAIL, whereas other breast cancer cell lines are resistant. The underlying mechanisms that control TRAIL sensitivity in breast cancer cells are not well understood. Here, we performed small interfering RNA (siRNA) screens to identify molecular regulators of the TRAIL pathway in breast cancer cells. Methods We conducted siRNA screens of the human kinome (691 genes), phosphatome (320 genes), and about 300 additional genes in the mesenchymal TNBC cell line MB231. Forty-eight hours after transfection of siRNA, parallel screens measuring caspase-8 activity, caspase-3/7 activity, or cell viability were conducted in the absence or presence of TRAIL for each siRNA, relative to a negative control siRNA (siNeg). A subset of genes was screened in cell lines representing epithelial TNBC (MB468), HER2-amplified breast cancer (SKBR3), and estrogen receptor-positive breast cancer (T47D). Selected putative negative regulators of the TRAIL pathway were studied by using small-molecule inhibitors. Results The primary screens in MB231 identified 150 genes, including 83 kinases, 4 phosphatases, and 63 nonkinases, as potential negative regulators of TRAIL. The identified genes are involved in many critical cell processes, including apoptosis, growth factor-receptor signaling, cell-cycle regulation, transcriptional regulation, and DNA repair. Gene-network analysis identified four genes (PDPK1, IKBKB, SRC, and BCL2L1) that formed key nodes within the interaction network of negative regulators. A secondary screen of a subset of the genes identified in additional cell lines representing different breast cancer subtypes and sensitivities to TRAIL validated and extended these findings. Further, we confirmed that small-molecule inhibition of SRC or BCL2L1, in combination with TRAIL, sensitizes breast cancer cells to TRAIL-induced apoptosis, including cell lines resistant to TRAIL-induced cytotoxicity. Conclusions These data identify novel molecular regulators of TRAIL-induced apoptosis in breast cancer cells and suggest strategies for the enhanced application of TRAIL as a therapy for breast cancer. PMID:24745479

2014-01-01

165

Frondoside A inhibits human breast cancer cell survival, migration, invasion and the growth of breast tumor xenografts.  

PubMed

Breast cancer is a major challenge for pharmacologists to develop new drugs to improve the survival of cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa. It has been demonstrated that Frondoside A inhibited the growth of pancreatic cancer cells in vitro and in vivo. We investigated the impact of Frondoside A on human breast cancer cell survival, migration and invasion in vitro, and on tumor growth in nude mice, using the human estrogen receptor-negative breast cancer cell line MDA-MB-231. The non-tumorigenic MCF10-A cell line derived from normal human mammary epithelium was used as control. Frondoside A (0.01-5 ?M) decreased the viability of breast cancer cells in a concentration- and time-dependent manner, with 50%-effective concentration (EC50) of 2.5 ?M at 24h. MCF10-A cells were more resistant to the cytotoxic effect of Frondoside A (EC50 superior to 5 ?M at 24 h). In the MDA-MB-231 cells, Frondoside A effectively increased the sub-G1 (apoptotic) cell fraction through the activation of p53, and subsequently the caspases 9 and 3/7 cell death pathways. In addition, Frondoside A induced a concentration-dependent inhibition of MDA-MB-231 cell migration and invasion. In vivo, Frondoside A (100 ?g/kg/dayi.p. for 24 days) strongly decreased the growth of MDA-MB-231 tumor xenografts in athymic mice, without manifest toxic side-effects. Moreover, we found that Frondoside A could enhance the killing of breast cancer cells induced by the chemotherapeutic agent paclitaxel. These findings identify Frondoside A as a promising novel therapeutic agent for breast cancer. PMID:21741966

Al Marzouqi, Nadia; Iratni, Rabah; Nemmar, Abderrahim; Arafat, Kholoud; Ahmed Al Sultan, Mahmood; Yasin, Javed; Collin, Peter; Mester, Jan; Adrian, Thomas E; Attoub, Samir

2011-10-01

166

BreastDefend(TM) prevents breast-to-lung cancer metastases in an orthotopic animal model of triple-negative human breast cancer  

PubMed Central

We have recently demonstrated that a natural dietary supplement BreastDefend (BD), which contains extracts from medicinal mushrooms (Coriolus versicolor, Ganoderma lucidum, Phellinus linteus), medicinal herbs (Scutellaria barbata, Astragalus membranaceus, Curcuma longa), and purified biologically active nutritional compounds (diindolylmethane and quercetin), inhibits proliferation and metastatic behavior of MDA-MB-231 invasive human breast cancer cells in vitro. In the present study, we evaluated whether BD suppresses growth and breast-to lung cancer metastasis in an orthotopic model of human breast cancer cells implanted in mice. Oral application of BD (100 mg/kg of body weight for 4 weeks) by intragastric gavage did not affect body weight or activity of liver enzymes and did not show any sign of toxicity in liver, spleen, kidney, lung and heart tissues in mice. Moreover, BD significantly decreased the change in tumor volume over time compared to the control group (p=0.002). BD treatment also markedly decreased the incidence of breast-to-lung cancer metastasis from 67% (control) to 20% (BD) (p<0.05) and the number of metastases from 2.8 (0.0, 48.0) in the control group to 0.0 (0.0, 14.2) in the BD treatment group (p<0.05). Finally, anti-metastatic activity of BD in vivo was further confirmed by the downregulation of expression of PLAU (urokinase plasminogen activator, uPA) and CXCR4 (C-X-C chemokine receptor-4) genes in breast tumors. In conclusion, BD may be considered as a biological therapeutic agent against invasive breast cancers. PMID:22842551

JIANG, JIAHUA; THYAGARAJAN-SAHU, ANITA; LOGANATHAN, JAGADISH; ELIAZ, ISAAC; TERRY, COLIN; SANDUSKY, GEORGE E.; SLIVA, DANIEL

2012-01-01

167

Automated quantification of aligned collagen for human breast carcinoma prognosis  

PubMed Central

Background: Mortality in cancer patients is directly attributable to the ability of cancer cells to metastasize to distant sites from the primary tumor. This migration of tumor cells begins with a remodeling of the local tumor microenvironment, including changes to the extracellular matrix and the recruitment of stromal cells, both of which facilitate invasion of tumor cells into the bloodstream. In breast cancer, it has been proposed that the alignment of collagen fibers surrounding tumor epithelial cells can serve as a quantitative image-based biomarker for survival of invasive ductal carcinoma patients. Specific types of collagen alignment have been identified for their prognostic value and now these tumor associated collagen signatures (TACS) are central to several clinical specimen imaging trials. Here, we implement the semi-automated acquisition and analysis of this TACS candidate biomarker and demonstrate a protocol that will allow consistent scoring to be performed throughout large patient cohorts. Methods: Using large field of view high resolution microscopy techniques, image processing and supervised learning methods, we are able to quantify and score features of collagen fiber alignment with respect to adjacent tumor-stromal boundaries. Results: Our semi-automated technique produced scores that have statistically significant correlation with scores generated by a panel of three human observers. In addition, our system generated classification scores that accurately predicted survival in a cohort of 196 breast cancer patients. Feature rank analysis reveals that TACS positive fibers are more well-aligned with each other, are of generally lower density, and terminate within or near groups of epithelial cells at larger angles of interaction. Conclusion: These results demonstrate the utility of a supervised learning protocol for streamlining the analysis of collagen alignment with respect to tumor stromal boundaries.

Bredfeldt, Jeremy S.; Liu, Yuming; Conklin, Matthew W.; Keely, Patricia J.; Mackie, Thomas R.; Eliceiri, Kevin W.

2014-01-01

168

Photothermal optical coherence tomography in ex vivo human breast tissues using gold nanoshells  

E-print Network

We demonstrate photothermal optical coherence tomography (OCT) imaging in highly scattering human breast tissue ex vivo. A 120 kHz axial scan rate, swept-source phase-sensitive OCT system at 1300 nm was used to detect phase ...

Zhou, Chao

169

Prolactin antagonist-endostatin fusion protein as a targeted dual-functional therapeutic agent for breast cancer.  

PubMed

In previous studies (Chen, W. Y. et al., Clin. Cancer Res., 5:3583-3593, 1999; Chen, N Y. et al., Int. J. Oncol., 20:813-818, 2002), we have demonstrated the ability of the human prolactin (hPRL) antagonist, G129R, to inhibit human breast cancer cell proliferation in vitro and to slow the growth rate of tumors in mice. We further revealed that the possible mechanisms of G129R antitumor effects act through the induction of apoptosis via the regulation of bcl-2 gene expression. It has been established that to sustain tumor growth, it is necessary for the development of a network of blood vessels to bring in nutrients, a process called angiogenesis. The disruption of angiogenesis has been proven to be an effective strategy to cause regression of certain tumors. One of the best-studied angiogenesis inhibitors is endostatin, which acts through the inhibition of endothelial cells. In this study, we combine the anti-breast tumor effects of G129R and the antiangiogenic effects of endostatin by creating a novel fusion protein (G129R-endostatin) specifically for breast cancer therapy. The data presented here demonstrated that this novel fusion protein was able to bind to the PRL receptor (PRLR) on T-47D human breast cancer cells and inhibit the signal transduction induced by PRL. At the same time, G129R-endostatin inhibited human umbilical vein endothelial cell (HUVEC) proliferation and disrupted the formation of endothelial tube structures with potency similar to that of endostatin. More importantly, the therapeutic efficacy of G129R-endostatin was confirmed using a mouse breast cancer cell line 4T1 in vivo. G129R-endostatin has a significantly prolonged serum half-life as compared with that of G129R or endostatin alone, and exhibited greater tumor inhibitory effects than G129R and endostatin individually or in combination. Taken together, these data demonstrate the dual therapeutic effects of G129R-endostatin, and suggests that this fusion protein has great promise as a novel anti-breast cancer agent. PMID:12839947

Beck, Michael T; Chen, Nian Y; Franek, Karl J; Chen, Wen Y

2003-07-01

170

Tissue Specific DNA Methylation in Normal Human Breast Epithelium and in Breast Cancer  

PubMed Central

Cancer is a heterogeneous and tissue-specific disease. Thus, the tissue of origin reflects on the natural history of the disease and dictates the therapeutic approach. It is suggested that tissue differentiation, mediated mostly by epigenetic modifications, could guide tissue-specific susceptibility and protective mechanisms against cancer. Here we studied breast specific methylation in purified normal epithelium and its reflection in breast cancers. We established genome wide methylation profiles of various normal epithelial tissues and identified 110 genes that were differentially methylated in normal breast epithelium. A number of these genes also showed methylation alterations in breast cancers. We elaborated on one of them, TRIM29 (ATDC), and showed that its promoter was hypo-methylated in normal breast epithelium and heavily methylated in other normal epithelial tissues. Moreover, in breast carcinomas methylation increased and expression decreased whereas the reverse was noted for multiple other carcinomas. Interestingly, TRIM29 regulation in breast tumors clustered according to the PAM50 classification. Thus, it was repressed in the estrogen receptor positive tumors, particularly in the more proliferative luminal B subtype. This goes in line with previous reports indicating tumor suppressive activity of TRIM29 in estrogen receptor positive luminal breast cells in contrast to oncogenic function in pancreatic and lung cancers. Overall, these findings emphasize the linkage between breast specific epigenetic regulation and tissue specificity of cancer. PMID:24651077

Avraham, Ayelet; Cho, Sean Soonweng; Uhlmann, Ronit; Polak, Mia Leonov; Sandbank, Judith; Karni, Tami; Pappo, Itzhak; Halperin, Ruvit; Vaknin, Zvi; Sella, Avishay; Sukumar, Saraswati; Evron, Ella

2014-01-01

171

Growth inhibitory activity of cucurbitacin glucosides isolated from Citrullus colocynthis on human breast cancer cells  

Microsoft Academic Search

Our aim was to study the effects of cucurbitacin glucosides extracted from Citrullus colocynthis leaves on human breast cancer cell growth. Leaves were extracted, resulting in the identification of cucurbitacin B\\/E glucosides. The cucurbitacin glucoside combination (1:1) inhibited growth of ER+ MCF-7 and ER? MDA-MB-231 human breast cancer cell lines. Cell-cycle analysis showed that treatment with isolated cucurbitacin glucoside combination

Tehila Tannin-Spitz; Shlomo Grossman; Sara Dovrat; Hugo E. Gottlieb; Margalit Bergman

2007-01-01

172

Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells  

Microsoft Academic Search

Estrogens play a crucial role in the development and evolution of human breast cancer. However, it is still unclear whether estrogens are carcinogenic to the human breast. There are three mechanisms that have been considered to be responsible for the carcinogenicity of estrogens: receptor-mediated hormonal activity, a cytochrome P450 (CYP)-mediated metabolic activation, which elicits direct genotoxic effects by increasing mutation

Jose Russo; M. Hasan Lareef; Gabriela Balogh; Shanchun Guo; Irma H. Russo

2003-01-01

173

Biodistribution and Predictive Value of 18F-Fluorocyclophosphamide in Mice Bearing Human Breast Cancer Xenografts  

Microsoft Academic Search

In mice bearing human breast cancer xenografts, we examined the biodistribution of 18F-fluorocyclophosphamide (18F-F-CP) to evaluate its potential as a noninvasive prognostic tool for pre- dicting the resistance of tumors to cyclophosphamide therapy. Methods: 18F-F-CP was synthesized as we recently described, and PET data were acquired after administration of 18F-F-CP in mice bearing human breast cancer xenografts (MCF-7 cells). Tracer

Amanda L. Kesner; Wei-Ann Hsueh; Nwe Linn Htet; Betty S. Pio; Johannes Czernin; Mark D. Pegram; Michael E. Phelps; Daniel H. S. Silverman

174

Insulin effects on methotrexate polyglutamate synthesis and enzyme binding in cultured human breast cancer cells  

Microsoft Academic Search

Summary Previous studies have demonstrated that insulin augments methotrexate transport and enhances its cytotoxicity to human breast cancer cells. We therefore investigated the effects of insulin on methotrexate polyglutamate synthesis and binding to dihydrofolate reductase (DHFR) in two human breast cancer cell lines, MCF-7 and MDA-MB-231. Cells were exposed to 2 ?M [3H]MTX and varying insulin concentrations for the desired

Richard L. Schilsky; Frederick S. Ordway

1985-01-01

175

Regulation of E2F-1 gene expression in human breast cancer cells  

E-print Network

REGULATION OF E2F-1 GENE EXPRESSION IN HUMAN BREAST CANCER CELLS A Dissertation by SHARON KHETHIWE NGWENYA Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements... for the degree of DOCTOR OF PHILOSOPHY May 2005 Major Subject: Biochemistry REGULATION OF E2F-1 GENE EXPRESSION IN HUMAN BREAST CANCER CELLS A Dissertation by SHARON KHETHIWE NGWENYA Submitted to Texas A&M University in partial...

Ngwenya, Sharon Khethiwe

2005-08-29

176

miRNA-34b as a tumor suppressor in estrogen-dependent growth of breast cancer cells  

PubMed Central

Introduction Estrogen is involved in several physiological and pathological processes through estrogen receptor (ER)-mediated transcriptional gene regulation. miRNAs (miRs), which are noncoding RNA genes, may respond to estrogen and serve as posttranscriptional regulators in tumorigenic progression, especially in breast cancer; however, only limited information about this possibility is available. In the present study, we identified the estrogen-regulated miR-34b and investigated its functional role in breast cancer progression. Methods Estrogen-regulated miRNAs were identified by using a TaqMan low density array. Our in vivo Tet-On system orthotopic model revealed the tumor-suppressive ability of miR-34b. Luciferase reporter assays and chromatin immunoprecipitation assay demonstrated miR-34b were regulated by p53-ER interaction. Results In this study, we identified one such estrogen downregulated miRNA, miR-34b, as an oncosuppressor that targets cyclin D1 and Jagged-1 (JAG1) in an ER+/wild-type p53 breast cancer cell line (MCF-7), as well as in ovarian and endometrial cells, but not in ER-negative or mutant p53 breast cancer cell lines (T47D, MBA-MB-361 and MDA-MB-435). There is a negative association between ER? and miR-34b expression levels in ER+ breast cancer patients. Tet-On induction of miR-34b can cause inhibition of tumor growth and cell proliferation. Also, the overexpression of miR-34b inhibited ER+ breast tumor growth in an orthotopic mammary fat pad xenograft mouse model. Further validation indicated that estrogen's inhibition of miR-34b expression was mediated by interactions between ER? and p53, not by DNA methylation regulation. The xenoestrogens diethylstilbestrol and zeranol also showed similar estrogenic effects by inhibiting miR-34b expression and by restoring the protein levels of the miR-34b targets cyclin D1 and JAG1 in MCF-7 cells. Conclusions These findings reveal that miR-34b is an oncosuppressor miRNA requiring both ER+ and wild-type p53 phenotypes in breast cancer cells. These results improve our ability to develop new therapeutic strategies to target the complex estrogenic pathway in human breast cancer progression through miRNA regulation. PMID:22113133

2011-01-01

177

Human Leukocyte Antigen-G (HLA-G) Polymorphism and Expression in Breast Cancer Patients  

PubMed Central

Human leukocyte antigen-G (HLA-G) is known to be implicated in a tumor-driven immune escape mechanism in malignancies. The purpose of this study was to investigate HLA-G polymorphism and expression in breast cancer. HLA-G alleles were determined by direct DNA sequencing procedures from blood samples of 80 breast cancer patients and 80 healthy controls. Soluble HLA-G (sHLA-G) was measured by enzyme-linked immunosorbent assay (ELISA) from serum specimens. HLA-G expression in breast cancer lesions was also analyzed by immunohistochemistry staining. The presence of HLA-G 3? untranslated region (UTR) 14-bp sequence was analyzed and found to be associated with reduced risk of breast cancer susceptibility based on HLA-G expression in tissues (P?=?0.0407). Levels of sHLA-G were higher in the breast cancer group (median 117.2 U/mL) compared to the control group (median 10.1 U/mL, P<0.001). The area under the receiver operating characteristic curve (AU-ROC) values of sHLA-G for differentiating breast cancer from normal controls and for detecting metastasis from other stages of breast cancer were 0.89 and 0.79, respectively. HLA-G polymorphism and expression may be involved in breast carcinogenesis and sHLA-G concentrations could be used as a diagnostic marker for detecting breast cancer. PMID:24870375

Jeong, Seri; Park, Seho; Park, Byeong-Woo; Park, Younhee; Kwon, Oh-Joong; Kim, Hyon-Suk

2014-01-01

178

Growth and metastasis of human breast carcinomas with Matrigel in athymic mice  

Microsoft Academic Search

Immunodeficient athymic mice with human tumor xenografts provide an importantin vivo experimental model for cancer research. However, only a limited number of tumor types grow in these animals. For human breast carcinomas, the incidence of tumor-take is 6–15%. Recently, increased incidence of xenograft development in mice has been reported for various human tumors when the tumors were coinjected with Matrigel.

Rajeshwari R. Mehta; Jewell M. Graves; Gloria D. Hart; Anne Shilkaitis; Tapas K. Gupta

1993-01-01

179

Combined photoacoustic and ultrasound imaging of human breast in vivo in the mammographic geometry  

NASA Astrophysics Data System (ADS)

This photoacoustic volume imaging (PAVI) system is designed to study breast cancer detection and diagnosis in the mammographic geometry in combination with automated 3D ultrasound (AUS). The good penetration of near-infrared (NIR) light and high receiving sensitivity of a broad bandwidth, 572 element, 2D PVDF array at a low center-frequency of 1MHz were utilized with 20 channel simultaneous acquisition. The feasibility of this system in imaging optically absorbing objects in deep breast tissues was assessed first through experiments on ex vivo whole breasts. The blood filled pseudo lesions were imaged at depths up to 49 mm in the specimens. In vivo imaging of human breasts has been conducted. 3D PAVI image stacks of human breasts were coregistered and compared with 3D ultrasound image stacks of the same breasts. Using the designed system, PAVI shows satisfactory imaging depth and sensitivity for coverage of the entire breast when imaged from both sides with mild compression in the mammographic geometry. With its unique soft tissue contrast and excellent sensitivity to the tissue hemodynamic properties of fractional blood volume and blood oxygenation, PAVI, as a complement to 3D ultrasound and digital tomosynthesis mammography, might well contribute to detection, diagnosis and prognosis for breast cancer.

Xie, Zhixing; Lee, Won-Mean; Hooi, Fong Ming; Fowlkes, J. Brian; Pinsky, Renee W.; Mueller, Dean; Wang, Xueding; Carson, Paul L.

2013-03-01

180

CITED2 modulates estrogen receptor transcriptional activity in breast cancer cells  

SciTech Connect

Highlights: •The effects of elevated CITED2 on ER function in breast cancer cells are examined. •CITED2 enhances cell growth in the absence of estrogen and presence of tamoxifen. •CITED2 functions as a transcriptional co-activator of ER in breast cancer cells. -- Abstract: Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) is a member of the CITED family of non-DNA binding transcriptional co-activators of the p300/CBP-mediated transcription complex. Previously, we identified CITED2 as being overexpressed in human breast tumors relative to normal mammary epithelium. Upon further investigation within the estrogen receptor (ER)-positive subset of these breast tumor samples, we found that CITED2 mRNA expression was elevated in those associated with poor survival. In light of this observation, we investigated the effect of elevated CITED2 levels on ER function. While ectopic overexpression of CITED2 in three ER-positive breast cancer cell lines (MCF-7, T47D, and CAMA-1) did not alter cell proliferation in complete media, growth was markedly enhanced in the absence of exogenous estrogen. Correspondingly, cells overexpressing CITED2 demonstrated reduced sensitivity to the growth inhibitory effects of the selective estrogen receptor modulator, 4-hydroxytamoxifen. Subsequent studies revealed that basal ER transcriptional activity was elevated in CITED2-overexpressing cells and was further increased upon the addition of estrogen. Similarly, basal and estrogen-induced expression of the ER-regulated genes trefoil factor 1 (TFF1) and progesterone receptor (PGR) was higher in cells overexpressing CITED2. Concordant with this observation, ChIP analysis revealed higher basal levels of CITED2 localized to the TFF-1 and PGR promoters in cells with ectopic overexpression of CITED2, and these levels were elevated further in response to estrogen stimulation. Taken together, these data indicate that CITED2 functions as a transcriptional co-activator of ER in breast cancer cells and that its increased expression in tumors may result in estrogen-independent ER activation, thereby reducing estrogen dependence and response to anti-estrogen therapy.

Lau, Wen Min; Doucet, Michele; Huang, David; Weber, Kristy L.; Kominsky, Scott L., E-mail: kominsc@jhmi.edu

2013-07-26

181

Estrogen Receptor Alpha in Human Breast Cancer: Occurrence and Significance  

Microsoft Academic Search

Estrogens have long been recognized as being important for stimulating the growth of a large proportion of breast cancers. Now it is recognized that estrogen action is mediated by two receptors, and the presence of estrogen receptor a (ERa)3 correlates with better prognosis and the likelihood of response to hormonal therapy. Over half of all breast cancers overexpress ERa and

Simak Ali; R. Charles Coombes

2000-01-01

182

Compensated individually addressable array technology for human breast imaging  

DOEpatents

A method of forming broad bandwidth acoustic or microwave beams which encompass array design, array excitation, source signal preprocessing, and received signal postprocessing. This technique uses several different methods to achieve improvement over conventional array systems. These methods are: 1) individually addressable array elements; 2) digital-to-analog converters for the source signals; 3) inverse filtering from source precompensation; and 4) spectral extrapolation to expand the bandwidth of the received signals. The components of the system will be used as follows: 1) The individually addressable array allows scanning around and over an object, such as a human breast, without any moving parts. The elements of the array are broad bandwidth elements and efficient radiators, as well as detectors. 2) Digital-to-analog converters as the source signal generators allow virtually any radiated field to be created in the half-space in front of the array. 3) Preprocessing allows for corrections in the system, most notably in the response of the individual elements and in the ability to increase contrast and resolution of signal propagating through the medium under investigation. 4) Postprocessing allows the received broad bandwidth signals to be expanded in a process similar to analytic continuation. Used together, the system allows for compensation to create beams of any desired shape, control the wave fields generated to correct for medium differences, and improve contract and resolution in and through the medium.

Lewis, D. Kent (San Francisco, CA)

2003-01-01

183

Down?regulation of gelsolin expression in human breast ductal carcinoma in situ with and without invasion  

Microsoft Academic Search

Expression of gelsolin, an actin filament regulatory protein, in human breast ductal carcinoma in situ (DCIS) was analyzed by immunohistochemistry using a monoclonal antibody. Formalin-fixed paraffin-embedded tissues from 59 pure DCIS specimens and 33 DCIS specimens with associated invasive components were evaluated for gelsolin reactivity and compared to eight normal breast cases and 76 invasive breast cancers. The proportion of

Harold L. Asch; Janet S. Winston; Stephen B. Edge; Paul C. Stomper; Bonnie B. Asch

1999-01-01

184

Nuclear magnetic resonance imaging and evaluation of human breast tissue: preliminary clinical trials  

SciTech Connect

In vivo clinical evaluations of human mammary tissue, including normal, dysplastic, and neoplastic breasts, were initiated using the FONAR method of nuclear magnetic resonance (NMR) imaging. Spin-lattice relaxation times (T/sub 1/) were determined and correlated with other diagnostic modalities including mammography, xeroradiography, and sonography. Normal breasts and breasts with extensive fatty replacement were found to have the lowest T/sub 1/ values, whereas T/sub 1/ values of malignant tissue were elevated. T/sub 1/ values for mammary dysplasia extended over a wide range, and NMR images exhibited lower proton density than normal tissues. In several patients with severely dysplastic breasts, T/sub 1/ values overlapped those from patients with documented breast neoplasms. Markedly elevated T/sub 1/ values were obtained from fluidfilled cysts that were well beyond the range of malignancy.

Ross, R.J.; Thompson, J.S.; Kim, K.; Bailey, R.A.

1982-04-01

185

VIS-NIR spectrum analysis for distinguishing tumor and normal human breast tissue  

NASA Astrophysics Data System (ADS)

The high incidence and mortality of breast cancer require an effective method for early breast diagnosis. In order to investigate the optical differences among malignant tumor, benign tumor and normal human breast tissue, a commercial spectrophotometer combined with single integrating sphere was used to measure the optical properties of different types of breast tissue in the wavelength range of 400 nm to 2200 nm in vitro. The hematoxylin and eosin staining (H&E staining) are used as the standard, and to find the find possible optical markers from the corresponding absorption or scattering spectra. This work is not only used for in vitro rapid optical diagnosis, but very helpful to develop innovative optical diagnosis of breast tumor in vivo.

Zhang, Yang; Yu, Yuan; Tuchin, Valery V.; Chen, Yongjun; Wen, Xiang; Liu, Caihua; Wang, Jing; Xue, Xingbo; Zhu, Dan

2012-03-01

186

Antagonism between estradiol and progestin on Bcl-2 expression in breast-cancer cells.  

PubMed

Bcl-2 is a key protein involved in the control of apoptosis. Our previous studies on breast and endometrium indicated hormonal regulation of bcl-2 in these tissues. In the present work we have analyzed Bcl-2 and Bax protein expressions in MCF-7 and T47-D, 2 hormone-dependent breast-cancer cell lines, by immunoblots. Estradiol markedly increased Bcl-2 protein content, both in short- and in long-term treatments of MCF-7 cells. Two types of anti-estrogens (4-hydroxytamoxifen and RU 58668) were able to reverse this effect. Also, a synthetic progestin (ORG 2058) was able to decrease the Bcl-2 level in T47-D cells. The level of Bax protein, however, was not affected in the same conditions of hormonal treatments. The level of Bcl-2 expression was 4.5-fold higher in MCF-7 than in MDA-MB 231 (an estradiol-independent cell line). From these results, we infer the existence of hormonal regulation of Bcl-2 expression and evoke a novel role for estradiol and progestin in the genesis of breast cancer. PMID:8895551

Kandouz, M; Siromachkova, M; Jacob, D; Chretien Marquet, B; Therwath, A; Gompel, A

1996-09-27

187

Analysis of HOX gene expression patterns in human breast cancer.  

PubMed

HOX genes are highly conserved transcription factors that determine the identity of cells and tissues along the anterior-posterior body axis in developing embryos. Aberrations in HOX gene expression have been shown in various tumors. However, the correlation of HOX gene expression patterns with tumorigenesis and cancer progression has not been fully characterized. Here, to analyze putative candidate HOX genes involved in breast cancer tumorigenesis and progression, the expression patterns of 39 HOX genes were analyzed using breast cancer cell lines and patient-derived breast tissues. In vitro analysis revealed that HOXA and HOXB gene expression occurred in a subtype-specific manner in breast cancer cell lines, whereas most HOXC genes were strongly expressed in most cell lines. Among the 39 HOX genes analyzed, 25 were chosen for further analysis in malignant and non-malignant tissues. Fourteen genes, encoding HOXA6, A13, B2, B4, B5, B6, B7, B8, B9, C5, C9, C13, D1, and D8, out of 25 showed statistically significant differential expression patterns between non-malignant and malignant breast tissues and are putative candidates associated with the development and malignant progression of breast cancer. Our data provide a valuable resource for furthering our understanding of HOX gene expression in breast cancer and the possible involvement of HOX genes in tumor progression. PMID:23820980

Hur, Ho; Lee, Ji-Yeon; Yun, Hyo Jung; Park, Byeong Woo; Kim, Myoung Hee

2014-01-01

188

Low levels of 3,3?-diindolylmethane activate estrogen receptor ? and induce proliferation of breast cancer cells in the absence of estradiol  

PubMed Central

Background 3,3?-diindolylmethane (DIM) is an acid-catalyzed dimer of idole-3-carbinol (I3C), a phytochemical found in cruciferous vegetables that include broccoli, Brussels sprouts and cabbage. DIM is an aryl hydrocarbon receptor (AhR) ligand and a potential anticancer agent, namely for the treatment of breast cancer. It is also advertised as a compound that regulates sex hormone homeostasis. Methods Here we make use of RNA expression assays coupled to Chromatin Immunoprecipitation (ChIP) in breast cancer cell lines to study the effect of DIM on estrogen signaling. We further make use of growth assays, as well as fluorescence-activated cell sorting (FACS) assays, to monitor cell growth. Results In this study, we report that ‘physiologically obtainable’ concentrations of DIM (10??M) activate the estrogen receptor ? (ER?) signaling pathway in the human breast cancer cell lines MCF7 and T47D, in a 17?-estradiol (E2)-independent manner. Accordingly, we observe induction of ER? target genes such as GREB1 and TFF1, and an increase in cellular proliferation after treatment with 10??M DIM in the absence of E2. By using an ER? specific inhibitor (ICI 182 780), we confirm that the transcriptional and proliferative effects of DIM treatment are mediated by ER?. We further show that the protein kinase A signaling pathway participates in DIM-mediated activation of ER?. In contrast, higher concentrations of DIM (e.g. 50??M) have an opposite and expected effect on cells, which is to inhibit proliferation. Conclusions We document an unexpected effect of DIM on cell proliferation, which is to stimulate growth by inducing the ER? signaling pathway. Importantly, this proliferative effect of DIM happens with potentially physiological concentrations that can be provided by the diet or by taking caplet supplements. PMID:25048790

2014-01-01

189

The T61 human breast cancer xenograft: An experimental model of estrogen therapy of breast cancer  

Microsoft Academic Search

Summary Endocrine therapy is one of the principal treatment modalities of breast cancer, both in an adjuvant setting and in advanced disease. The T61 breast cancer xenograft described here provides an experimental model of the effects of estrogen treatment at a molecular level. T61 is an estrogen receptor positive tumor which was originally derived from a T1N0M0 invasive ductal cancer

Nils Briinner I; Mogens Spang-Thomsen; Kevin Cullen

1996-01-01

190

Breastfeeding: breast milk banks and human immunodeficiency virus.  

PubMed

HIV in infants and children in Zimbabwe is virtually limited to vertical transmission. Less than 5 cases of transfusion acquired HIV infections have been documented to date. Zimbabwe was the third country in the world after the United States, to screen transfusion blood and blood products. The controversy of HIV transmission through breast milk is still far from resolved. In developing countries, breast-milk substitutes for formulae are not only prohibitively expensive but dangerous because of unhygienic and economic constraints. The paper argues the case for continued breast-feeding of infants by their HIV seropositive mothers. PMID:2092885

Choto, R G

1990-12-01

191

Expression of Human Endogenous Retrovirus Type K Envelope Protein is a Novel Candidate Prognostic Marker for Human Breast Cancer  

PubMed Central

We previously observed that the HERV type K (HERV-K) envelope (env) protein was expressed in the majority of human breast tumors from a U.S. cohort of women from Texas. We also made the preliminary observation that the expression of HERV-K env transcripts was associated with markers of disease progression. In this follow-up study, env protein expression was evaluated immunohistochemically in an additional 195 paraffin-embedded breast tumors from a second U.S. patient cohort (Baltimore, Maryland) and in 110 tumors from Chinese patients. Moreover, we compared env transcript expression between fresh-frozen normal and cancerous breast tissues. We observed that while env mRNA and protein expression was undetectable in normal breast tissue and in a subset of uninvolved normal-appearing tissue adjacent to the tumor epithelium, it was overexpressed in most tumors. Furthermore, env expression was associated with breast cancer progression. In Baltimore cohort women, HERV-K tumor positivity was significantly associated with disease stage and lymph node metastasis. In Chinese women, HERV-K env positivity was significantly associated with tumor size, TNM stage, and lymph node metastases, which is consistent with the observations in the U.S. cohort. We also found that Chinese breast cancer patients with a high expression of HERV-K had a decreased overall survival compared with patients who had either a moderate or low HERV-K expression in their tumors (P = 0.049, ?2 log rank test). In conclusion, the HERV-K env gene is expressed in the majority of breast cancers from U.S. or Chinese women but not in normal breast tissue. High expression of HERV-K env protein in breast cancer patients is associated with markers of disease progression and poor disease outcome, indicating that HERV-K env protein is a novel candidate prognostic marker for breast cancer. PMID:22593804

Zhao, Jing; Rycaj, Kiera; Geng, Shanshan; Li, Ming; Plummer, Joshua B.; Yin, Bingnan; Liu, Hong; Xu, Xu; Zhang, Yinchun; Yan, Yanfang; Glynn, Sharon A.; Dorsey, Tiffany H.; Ambs, Stefan; Johanning, Gary L.; Gu, Lin

2011-01-01

192

Cloning and expression of full-length cDNA encoding human vitamin D receptor  

Microsoft Academic Search

Complementary DNA clones encoding the human vitamin D receptor have been isolated from human intestine and T47D cell cDNA libraries. The nucleotide sequence of the 4605-base pair (bp) cDNA includes a noncoding leader sequence of 115 bp, a 1281-bp open reading frame, and 3209 bp of 3â² noncoding sequence. Two polyadenylylation signals, AATAAA, are present 25 and 70 bp upstream

A. R. Baker; D. P. McDonnell; M. Hughes; T. M. Crisp; D. J. Mangelsdorf; M. R. Haussler; J. W. Pike; J. Shine; B. W. OMalley

1988-01-01

193

Paradoxical effect of estradiol: it can block its own bioformation in human breast cancer cells  

Microsoft Academic Search

The great majority of breast cancers are in their early stage hormone-dependent and it is well accepted that estradiol (E2) plays an important role in the genesis and evolution of this tumor. Human breast cancer tissues contain all the enzymes: estrone sulfatase, 17?-hydroxysteroid dehydrogenase (17?-HSD), aromatase, involved in the last steps of E2 bioformation in this tissue. Quantitative data show

J. R. Pasqualini; G. Chetrite

2001-01-01

194

Quantification of naturally occurring benzodiazepine-like substances in human breast milk  

Microsoft Academic Search

The possible occurrence of benzodiazepine-like substances in human breast milk was investigated in 35 healthy, newly delivered women who were known not to be taking benzodiazepines. Maternal blood samples and a sample of breast milk were obtained on the fifth post partum day. A radioreceptor technique (lower limit of detection 1.5 ng\\/ml; difference between duplicates at various concentrations <7%) was

Sven J. Dencker; Gunvor Johansson; Ian Milsom

1992-01-01

195

Claudin-20 promotes an aggressive phenotype in human breast cancer cells  

PubMed Central

Claudin-20 is a member of the Claudin family of transmembrane proteins located in the tight junction (TJ) of cells of epithelial origin. Due to the increasing evidence supporting the role of TJ proteins in preventing tumor cell metastatic behavior, this study sought to evaluate the distribution of Claudin-20 in human breast cancer and the effect of Claudin-20 overexpression in human breast cancer cells. Q-PCR data from breast cancer primary tumors (n = 114) and matched background tissue (n = 30) showed that high claudin-20 expression was correlated with poor survival of patients with breast cancer (p = 0.022). Following transformation of the breast cancer cell lines MDA-MB-231 and MCF7 with a Claudin-20 expression construct functional assays were performed to ascertain changes in cell behavior. Claudin-20 transformed cells showed significantly increased invasion (p < 0.005) and were significantly less adhesive than wild type cells (p < 0.05). There was no effect on growth (either in vitro or in vivo) for either cell line. Overexpression of Claudin-20 resulted in reduced transepithelial resistance (induced by the motogen HGF at 25 ng/ml, p = 0.0007). Interestingly, this was not mirrored by paracellular permeability, as overexpression of Claudin-20 caused a decrease in permeability. The introduction of Claudin-20 into human breast cancer cells resulted in breast cancer cells with an aggressive phenotype and reduced trans-epithelial resistance. There was no corresponding decrease in paracellular permeability, indicating that this Claudin has a differential function in epithelial TJ. This provides further insight into the importance of correctly functioning TJ in preventing the progression of human breast cancer. PMID:24665404

Martin, Tracey A; Lane, Jane; Ozupek, Hulya; Jiang, Wen G

2013-01-01

196

Oxidative DNA Damage and Repair in a Cell Lineage Model of Human Proliferative Breast Disease (PBD)  

Microsoft Academic Search

Oxidative damage to DNA is thought to play a significant role in mutagenesis, aging, and cancer. Sensitivity to oxidative DNA damage and DNA repair efficiency were examined using a series of human breast epithelial cell lines—MCF-10A, MCF-10AT, and MCF-10ATG3B—with progressively elevated Ras protein. Breast epithelial cells were treated with H2O2, in the absence and pres- ence of the DNA-repair inhibitors

Susan L. Starcevic; Nicole M. Diotte; Kim L. Zukowski; Mark J. Cameron; Raymond F. Novak

2003-01-01

197

Studies of the HER2\\/neu ProtoOncogene in Human Breast and Ovarian Cancer  

Microsoft Academic Search

Carcinoma of the breast and ovary account for one-third of all cancers occurring in women and together are responsible for approximately one-quarter of cancer-related deaths in females. The HER-2\\/neu proto-oncogene is amplified in 25 to 30 percent of human primary breast cancers and this alteration is associated with disease behavior. In this report, several similarities were found in the biology

Dennis J. Slamon; William Godolphin; Lovell A. Jones; John A. Holt; Steven G. Wong; Duane E. Keith; Wendy J. Levin; Susan G. Stuart; Judy Udove; Axel Ullrich

1989-01-01

198

Cyclooxygenase2 Expression in Human Breast Cancers and Adjacent Ductal Carcinoma in Situ1  

Microsoft Academic Search

Cyclooxygenase-2 (COX-2) is an inducible enzyme that converts arachi- donic acid to prostaglandins. Overexpression of the COX-2 gene in mam- mary glands of transgenic mice was sufficient to induce tumorigenesis. We analyzed COX-2 expression in human breast cancers (and breast cancer cell lines) and adjacent ductal carcinoma in situ (DCIS) as well as its association with HER2\\/neu and clinicopathological variables.

Elizabeth Half; Xi Ming Tang; Karin Gwyn; Aysegul Sahin; Kyle Wathen; Frank A. Sinicrope

2002-01-01

199

erbB3 recruitment of insulin receptor substrate 1 modulates insulin-like growth factor receptor signalling in oestrogen receptor-positive breast cancer cell lines  

PubMed Central

Introduction Recently we reported that insulin receptor substrate 1 (IRS-1), classically an adaptor protein for the insulin-like growth factor type I receptor (IGF-IR), associates with the epidermal growth factor receptor in oestrogen receptor (ER)-positive (ER+) tamoxifen-resistant breast cancer cells. In this study, we examined whether IRS-1 also associates with another erbB receptor family member, erbB3, and what impact this might have on IGF-IR signalling in three ER+ breast cancer cell lines. Methods Immunoprecipitation and Western blot analysis were utilised to examine the potential association between erbB3 and IRS-1 in MCF-7, T47D and BT-474 cells in the absence and presence of the erbB3/4 ligand heregulin ?1 (HRG?1). Subsequently, the impact of a selective IGF-IR/IR inhibitor 4-anilino-5-bromo-2-[4-(2-hydroxy-3-(N, N-dimethylamino)propoxy)anilino]pyrimidine on this association and HRG?1 signalling was assessed in these cell lines. Immunohistochemical analysis of a small cohort of ER+ breast cancer patient samples was also performed to determine the potential clinical relevance of this novel interaction. Results Immunoprecipitation and Western blot analysis revealed an interaction between erbB3 and IRS-1 in MCF-7, T47D and BT-474 cells, with HRG?1 significantly enhancing this recruitment and promoting IRS-1 phosphorylation at Y612. IRS-1 participates in erbB3 signalling in MCF-7 and T47D cells as IRS-1 knockdown impaired HRG?1 signalling. Importantly, recruitment of IRS-1 by erbB3 reduced IRS-1 association with IGF-IR in MCF-7 and T47D cells, whilst blockade of IGF-IR-enhanced erbB3-IRS-1 interaction and sensitised both cell lines to HRG?1, allowing HRG?1 to override IGF-IR blockade. Consequently, suppression of IRS-1 signalling enhanced the effects of IGF-IR inhibition in these cells. This novel interaction may have clinical relevance, as immunohistochemical analysis of a small ER+ breast tumour series revealed significant positive correlations between phosphorylated IRS-1 Y612 expression and total erbB3, phosphorylated Akt and Ki-67 expression. Conclusions IRS-1 can be recruited to IGF-IR and erbB3 in ER+ breast cancer cells, and this provides an adaptive resistance mechanism when these receptors are targeted individually. Consequently, cotargeting IGF-IR and either erbB3 or IRS-1 should prove to be a more effective strategy for the treatment of ER+ breast cancer. PMID:21939528

2011-01-01

200

PRECLINICAL STUDY Adult human mesenchymal stem cells enhance breast  

E-print Network

in the presence or absence of estrogen in SCID/beige mice. We also show hormone-independent growth of MCF-7 cells and eosin SCID Severe combined immunodeficiency SDF-1 Stromal-derived factor 1 Introduction Breast cancer

McLachlan, John

201

Progesterone receptor enhances breast cancer cell motility and invasion via extranuclear activation of focal adhesion kinase.  

PubMed

While progesterone plays multiple roles in the process of breast development and differentiation, its role in breast cancer is less understood. We have shown previously that progestins stimulate breast cancer cell migration and invasion because of the activation of rapid signaling cascades leading to modifications in the actin cytoskeleton and cell membrane that are required for cell movement. In this study, we have investigated the effects of progesterone on the formation of focal adhesion (FA) complexes, which provide anchoring sites for cell attachment to the extracellular matrix during cell movement and invasion. In T47-D breast cancer cells, progesterone rapidly enhances FA kinase (FAK) phosphorylation at Tyr(397) in a time- and concentration-dependent manner. As a result, exposure to progesterone leads to increased formation of FA complexes within specialized cell membrane protrusions. The cascade of events required for this phenomenon involves progesterone receptor interaction with the tyrosine kinase c-Src, which activates the phosphatidylinositol-3-kinase/Akt pathway and the small GTPase RhoA/Rho-associated kinase complex. In the presence of progesterone, T47-D breast cancer cells display enhanced horizontal migration and invasion of three-dimensional matrices, which is reversed by small interfering RNAs abrogating FAK. In conclusion, progesterone promotes breast cancer cell movement and invasion by facilitating the formation of FA complexes via the rapid regulation of FAK. These results provide novel mechanistic views on the effects of progesterone on breast cancer progression, and may in the future be helpful to develop new strategies for the treatment of endocrine-sensitive breast cancers. PMID:20233709

Fu, Xiao-Dong; Goglia, Lorenzo; Sanchez, Angel Matias; Flamini, Marina; Giretti, Maria S; Tosi, Veronica; Genazzani, Andrea R; Simoncini, Tommaso

2010-06-01

202

Human breast cancer cells share antigens with the myeloid monocyte lineage.  

PubMed Central

We have examined the expression of several myeloid cell associated antigens, some of which are involved in myelomonocyte adhesion, in seven well characterized human breast cancer cell lines, since common properties of adhesiveness and migration are found in haemopoietic cells and epithelial cancer cells. Five of these cell lines were of metastatic origin and two were derived from primary breast carcinoma. Antigenic expression was evaluated by immunofluorescence (IF), flow cytometry (FCM), radioimmunoassay on live cells (RIA) and immunoperoxidase staining. None of these cell lines expressed T or B lymphoid specific antigens. Myeloid antigens My4, MO1, and MOF11 (derived from the hybridization of mouse X63 - Ag8 cells with spleen cells from Balb/c mice immunized with purified human monocytes) were expressed in the 7 cell lines. Leu M1, Leu M3, My9, and MO2 antigens were expressed in some of the cell lines. Leu M2 and My7 antigens were not expressed or at very low levels. The expression of these myeloid antigens was also tested by immunoperoxidase staining, and found on frozen sections of normal mammary gland, fibroadenoma of the breast, primary breast cancer, and lymph node and skin metastases of breast tumours. This common expression in epithelial breast cells and in myeloid cells might be related to common biological functions such as interaction with extracellular matrix which precedes cell migration, a normal function of macrophages and an abnormal function expressed or amplified in human cancer epithelial cells. Images Figure 2 PMID:3304388

Calvo, F.; Martin, P. M.; Jabrane, N.; De Cremoux, P.; Magdelenat, H.

1987-01-01

203

Organophosphorus flame retardants (PFRs) in human breast milk from several Asian countries.  

PubMed

In this study, the concentrations of 10 organophosphorus flame retardants (PFRs) were determined in 89 human breast milk samples collected from Japan, the Philippines and Vietnam. Among the targeted PFRs, tris(2-chloroexyl) phosphate (TCEP) and triphenyl phosphate (TPHP) were the predominant compounds and were detected in more than 60% of samples in all three countries. The concentrations of PFRs in human breast milk were significantly higher (p<0.05) in the Philippines (median 70ngg(-1)lipidwt.) than those in Japan (median 22ngg(-1)lipidwt.) and Vietnam (median 10ngg(-1)lipidwt.). The present results suggest that the usage of products containing PFRs in the Philippines is higher than those of Japan and Vietnam. Comparing with a previous literature survey in Sweden, the levels of PFRs in human breast milk from the Philippines were 1.5-2 times higher, whereas levels in Japan and Vietnam were 4-20 times lower, suggesting that these differences might be due to their variation in the usage of flame-retarded products utilized in each country. When daily intake of PFRs to infants via human breast milk was estimated, some individuals accumulated tris(2-butoxyethyl) phosphate (TBOEP) and TCEP were close to reference dose (RfD). This is the first report to identify PFRs in human breast milk samples from Asian countries. PMID:24630247

Kim, Joon-Woo; Isobe, Tomohiko; Muto, Mamoru; Tue, Nguyen Minh; Katsura, Kana; Malarvannan, Govindan; Sudaryanto, Agus; Chang, Kwang-Hyeon; Prudente, Maricar; Viet, Pham Hung; Takahashi, Shin; Tanabe, Shinsuke

2014-12-01

204

Revisiting a role for a mammary tumor retrovirus in human breast cancer.  

PubMed

There remains great controversy as to whether mouse mammary tumor virus (MMTV), the etiological agent of mammary cancer in mice, or a closely related human retrovirus, plays a role in the development of breast cancer in humans. On one hand, retroviruses such as human T-cell lymphotropic virus and human immunodeficiency virus (HIV) are known causative agents of cancer (in the case of HIV, albeit, indirectly), but attempts to associate other retroviruses with human cancers have been difficult. A recent, high profile, example has been the postulated involvement of another mouse virus, xenotropic murine leukemia virus-related virus, in human prostate cancer, which is now thought to be due to contamination. Here, we review some of the more recent evidence for and against the involvement of MMTV in human breast cancer and suggest future studies that may allow a definitive answer to this conundrum. PMID:23580334

Salmons, Brian; Gunzburg, Walter H

2013-10-01

205

Survivin family proteins as novel molecular determinants of doxorubicin resistance in organotypic human breast tumors  

PubMed Central

Introduction The molecular determinants of breast cancer resistance to first-line anthracycline-containing chemotherapy are unknown. Methods We examined the response to doxorubicin of organotypic cultures of primary human breast tumors ex vivo with respect to cell proliferation, DNA damage and modulation of apoptosis. Samples were analyzed for genome-wide modulation of cell death pathways, differential activation of p53, and the role of survivin family molecules in drug resistance. Rational drug combination regimens were explored by high-throughput screening, and validated in model breast cancer cell types. Results Doxorubicin treatment segregated organotypic human breast tumors into distinct Responder or Non Responder groups, characterized by differential proliferative index, stabilization of p53, and induction of apoptosis. Conversely, tumor histotype, hormone receptor or human epidermal growth factor receptor-2 (HER2) status did not influence chemotherapy sensitivity. Global analysis of cell death pathways identified survivin and its alternatively spliced form, survivin-?Ex3 as uniquely overexpressed in Non Responder breast tumors. Forced expression of survivin-?Ex3 preserved cell viability and prevented doxorubicin-induced apoptosis in breast cancer cell types. High-throughput pharmacologic targeting of survivin family proteins with a small-molecule survivin suppressant currently in the clinic (YM155) selectively potentiated the effect of doxorubicin, but not other chemotherapeutics in breast cancer cell types, and induced tumor cell apoptosis. Conclusions Survivin family proteins are novel effectors of doxorubicin resistance in chemotherapy-naive breast cancer. The incorporation of survivin antagonist(s) in anthracycline-containing regimens may have improved clinical activity in these patients. PMID:24886669

2014-01-01

206

EVIDENCE FOR THE PRESENCE OF MUTAGENIC ARYL AMINES IN HUMAN BREAST MILK AND DNA ADDUCTS IN EXFOLIATED BREAST-DUCT EPITHELIAL CELLS  

EPA Science Inventory

Aromatic (AA) and heterocyclic amines (HAA) are ubiquitous environmental mutagens present in combustions emissions, fried meats, tobacco smoke, etc., and are suspect human mammary carcinogens. To determine the presence of aryl amines in breast tissue and fluid, we examined exfol...

207

Amplification and over-expression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells.  

PubMed

Gene amplifications in the 17q chromosomal region are observed frequently in breast cancers. An integrative bioinformatics analysis of this region nominated the MAP3K3 gene as a potential therapeutic target in breast cancer. This gene encodes mitogen-activated protein kinase kinase kinase 3 (MAP3K3/MEKK3), which has not yet been reported to be associated with cancer-causing genetic aberrations. We found that MAP3K3 was amplified in approximately 8-20% of breast cancers. Knockdown of MAP3K3 expression significantly inhibited cell proliferation and colony formation in MAP3K3-amplified breast cancer cell lines MCF-7 and MDA-MB-361 but not in MAP3K3 non-amplified breast cancer cells. Knockdown of MAP3K3 expression in MAP3K3-amplified breast cancer cells sensitized breast cancer cells to apoptotic induction by TNF? and TRAIL, as well as doxorubicin, VP-16 and fluorouracil, three commonly used chemotherapeutic drugs for treating breast cancer. In addition, ectopic expression of MAP3K3, in collaboration with Ras, induced colony formation in both primary mouse embryonic fibroblasts and immortalized human breast epithelial cells (MCF-10A). Combined, these results suggest that MAP3K3 contributes to breast carcinogenesis and may endow resistance of breast cancer cells to cytotoxic chemotherapy. Therefore, MAP3K3 may be a valuable therapeutic target in patients with MAP3K3-amplified breast cancers, and blocking MAP3K3 kinase activity with a small molecule inhibitor may sensitize MAP3K3-amplified breast cancer cells to chemotherapy. PMID:24122835

Fan, Yihui; Ge, Ningling; Wang, Xiaosong; Sun, Wenjing; Mao, Renfang; Bu, Wen; Creighton, Chad J; Zheng, Pingju; Vasudevan, Sanjeev; An, Lei; Yang, Jinshu; Zhao, Yi-Jue; Zhang, Huiyuan; Li, Xiao-Nan; Rao, Pulivarthi H; Leung, Eastwood; Lu, Yong-Jie; Gray, Joe W; Schiff, Rachel; Hilsenbeck, Susan G; Osborne, C Kent; Yang, Jianhua; Zhang, Hong

2014-01-01

208

Inhibition of Skeletal Metastasis by Ectopic ER? Expression in ER?-Negative Human Breast Cancer Cell Lines  

Microsoft Academic Search

Some hormone-independent breast cancers lack func- tional estrogen receptors (ERs) and show evidence of a more aggressive metastatic phenotype. A protective role of the ER has also been suggested in hormone- resistant breast cancer progression. In this study, we have investigated the effect of the ectopic expression of human ERA on the bone-metastatic potential of highly metastatic ERA-negative human breast

Abhik Bandyopadhyay; Long Wang; Shiau Hui Chin; Lu-Zhe Sun

2007-01-01

209

Hepatoma upregulated protein expression is involved in the pathogenesis of human breast carcinogenesis  

PubMed Central

In the last decade, the overexpression of hepatoma upregulated protein (HURP) has been reported in hepatocellular carcinoma, adrenocortical tumors and urogenital carcinoma. However, the role of HURP in breast cancer remains unknown. In the present study, a comprehensive analysis was performed to examine the HURP expression level in 43 breast cancer tumor samples and paired adjacent normal tissues. The correlation between the HURP expression level and the clinicopathological characteristics was evaluated. The role of HURP in breast cancer was investigated by quantitative polymerase chain reaction, western blot analysis and cell proliferation assays. HURP expression was found to be significantly increased in the breast cancer samples. The HURP expression level was higher in the tumors with advanced-grade metastasis and was strongly associated with tumor-node-metastasis staging (P=0.003). Transfection and cell proliferation assays suggested that the suppression of HURP expression or the interference in HURP activity in the breast cancer cells inhibited cell proliferation significantly. These data suggest that HURP is associated with the degree of malignancy and the proliferation of breast cancer. HURP could be a tumor biomarker for prognosis and a potential therapeutic drug target for human breast cancer. PMID:25364424

CHEN, JIN; LIU, QIU-JUN; WANG, DA; ZHOU, XIAN-YAO; XIONG, DING; LI, HONG-JIANG; LI, CHANG-LONG

2014-01-01

210

Skp2 Regulates Subcellular Localization of PPAR? by MEK Signaling Pathways in Human Breast Cancer  

PubMed Central

Nuclear hormone receptor family member PPAR? plays an important role in mammary gland tumorigenesis. Previous studies have shown PPAR? has cytoplasmic activities upon tetradecanoyl phorbol acetate (TPA) stimulation. However, the clinical pathological significance of cytoplasmic PPAR? is not completely understood in human breast cancer. Skp2 is oncogenic, and its frequent amplification and overexpression correlated with the grade of malignancy. In this study, the role of cytoplasmic PPAR? and Skp2 expression was investigated in human breast cancer progression. Therefore, immunohistochemical analysis was performed on formalin-fixed paraffin sections of 70 specimens. Furthermore, Western blot and immunofluorescence microscopy analysis were used to study the relationship between expression of cytoplasmic PPAR? and Skp2 expression in human breast cancer cells in vitro. Results showed that the expression of cytoplasmic PPAR? was positively correlated with Skp2 expression (p < 0.05), and correlated significantly with estrogen receptor (p = 0.026) and pathological grade (p = 0.029), respectively. In addition, Skp2 overexpression can provoke cytoplasmic localization of PPAR? upon MEK1-dependent mechanisms in human breast cancer cells by nuclear-cytosolic fractionation technology and immunofluorescence microscopy analysis. Using RNA interference technology, we also found that down-regulated Skp2 reduced the phosphorylation level of MEK1 and significantly reversed TPA-induced nuclear export of PPAR? in MDA-MB-231 cells. The changes in the subcellular localization of PPAR? may represent a novel target for selective interference in patients with breast cancer. PMID:23939428

Cheng, Hongge; Meng, Jie; Wang, Guisheng; Meng, Yuming; Li, Yu; Wei, Dong; Fu, Chunyun; Deng, Kaifeng; Shen, Aiguo; Wang, Huimin; Dai, Shengming

2013-01-01

211

Anatomy of the lactating human breast redefined with ultrasound imaging  

PubMed Central

The aim of this study was to use ultrasound imaging to re-investigate the anatomy of the lactating breast. The breasts of 21 fully lactating women (1–6 months post partum) were scanned using an ACUSON XP10 (5–10 MHz linear array probe). The number of main ducts was measured, ductal morphology was determined, and the distribution of glandular and adipose tissue was recorded. Milk ducts appeared as hypoechoic tubular structures with echogenic walls that often contained echoes. Ducts were easily compressed and did not display typical sinuses. All ducts branched within the areolar radius, the first branch occurring 8.0 ± 5.5 mm from the nipple. Duct diameter was 1.9 ± 0.6 mm, 2.0 ± 90.7 mm and the number of main ducts was 9.6 ± 2.9, 9.2 ± 2.9, for left and right breast, respectively. Milk ducts are superficial, easily compressible and echoes within the duct represent fat globules in breastmilk. The low number and size of the ducts, the rapid branching under the areola and the absence of sinuses suggest that ducts transport breastmilk, rather than store it. The distribution of adipose and glandular tissue showed wide variation between women but not between breasts within women. The proportion of glandular and fat tissue and the number and size of ducts were not related to milk production. This study highlights inconsistencies in anatomical literature that impact on breast physiology, breastfeeding management and ultrasound assessment. PMID:15960763

Ramsay, DT; Kent, JC; Hartmann, RA; Hartman, PE

2005-01-01

212

Lectin of Abelmoschus esculentus (okra) promotes selective antitumor effects in human breast cancer cells.  

PubMed

The anti-tumor effects of a newly-discovered lectin, isolated from okra, Abelmoschus esculentus (AEL), were investigated in human breast cancer (MCF7) and skin fibroblast (CCD-1059 sk) cells. AEL induced significant cell growth inhibition (63 %) in MCF7 cells. The expression of pro-apoptotic caspase-3, caspase-9, and p21 genes was increased in MCF7 cells treated with AEL, compared to those treated with controls. In addition, AEL treatment increased the Bax/Bcl-2 ratio in MCF7 cells. Flow cytometry also indicated that cell death (72 %) predominantly occurred through apoptosis. Thus, AEL in its native form promotes selective antitumor effects in human breast cancer cells and may represent a potential therapeutic to combat human breast cancer. PMID:24129958

Monte, Leonardo G; Santi-Gadelha, Tatiane; Reis, Larissa B; Braganhol, Elizandra; Prietsch, Rafael F; Dellagostin, Odir A; E Lacerda, Rodrigo Rodrigues; Gadelha, Carlos A A; Conceição, Fabricio R; Pinto, Luciano S

2014-03-01

213

Immunocytochemical localization of insulin- and somatostatin-like material in human breast tumors.  

PubMed

Four types of human breast lesions and C3H mouse mammary adenocarcinomas (type A) were examined for the immunocytochemical localization of cells containing hormone-like substances. Insulin- or somatostatin-like immunoreactive material was observed in scattered single cells and nests of tumor cells in seven of eight infiltrating duct carcinomas, and in the majority of tumor cells from an anaplastic carcinoma. A few somatostatin-immunoreactive cells were observed in only one of seven fibroadenomas studied. No immunoreactive cells were observed in mouse adenocarcinomas or in human breast dysplasias. These results suggest that cells with hormone-like immunoreactivity may be a common feature in two types of malignant human breast tumors. PMID:6376992

Spring-Mills, E J; Stearns, S B; Numann, P J; Smith, P H

1984-07-01

214

The Role and Regulatory Mechanism of 14-3-3 Sigma in Human Breast Cancer  

PubMed Central

Purpose 14-3-3 sigma (?) is considered to be an important tumor suppressor and decreased expression of the same has been reported in many malignant tumors by hypermethylation at its promoter or ubiquitin-mediated proteolysis by estrogen-responsive ring finger protein (Efp). In this study, we investigated the significance of 14-3-3 ? expression in human breast cancer and its regulatory mechanism. Methods Efp was silenced using small interfering RNA (siRNA) in the MCF-7 breast cancer cell line in order to examine its influence on the level of 14-3-3 ? protein. The methylation status of the 14-3-3 ? promoter was also evaluated by methylation-specific polymerase chain reaction (PCR). The expression of Efp and 14-3-3 ? in 220 human breast carcinoma tissues was assessed by immunohistochemistry. Other clinicopathological parameters were also evaluated. Results Silencing Efp in the MCF-7 breast cancer cell line resulted in increased expression of 14-3-3 ?. The Efp-positive human breast cancers were more frequently 14-3-3 ?-negative (60.5% vs. 39.5%). Hypermethylation of 14-3-3 ? was common (64.9%) and had an inverse association with 14-3-3 ? positivity (p=0.072). Positive 14-3-3 ? expression was significantly correlated with poor prognosis: disease-free survival (p=0.008) and disease-specific survival (p=0.009). Conclusion Our data suggests that in human breast cancer, the regulation of 14-3-3 ? may involve two mechanisms: ubiquitin-mediated proteolysis by Efp and downregulation by hypermethylation. However, the inactivation of 14-3-3 ? is probably achieved mainly by hypermethylation. Interestingly, 14-3-3 ? turned out to be a very significant poor prognostic indicator, which is in contrast to its previously known function as a tumor suppressor, suggesting a different role of 14-3-3 ? in breast cancer.

Ko, SeungSang; Kim, Ji Young; Jeong, Joon; Lee, Jong Eun; Yang, Woo Ick

2014-01-01

215

COMBINED PHOTO-ACOUSTIC AND ACOUSTIC IMAGING OF HUMAN BREAST SPECIMENS IN THE MAMMOGRAPHIC GEOMETRY  

PubMed Central

A photo-acoustic volume imaging (PAVI) system was designed to study breast cancer detection and diagnosis in the mammographic geometry in combination with automated 3-D ultrasound (AUS). The goal of the work described here was to validate the design and evaluate its performance in human breast tissues for non-invasive imaging of deeply positioned structures covering such geometry. The good penetration of nearinfrared light and high receiving sensitivity of a broad-bandwidth, 572-element, 2-D poly(vinyl difluoride) array at a low center frequency of 1 MHz were used with 20 channel simultaneous acquisition. Pseudo-lesions filled with dilute blood were imaged in three human breast specimens at various depths up to 49 mm. With near-infrared light illumination and 256-sample averaging, the extrapolated maximum depth in imaging a 2.4-mm blood-rich lesion with a 3-dB contrast-to-noise ratio in a compressed breast was 54 mm. Three-dimensional photo-acoustic volume image stacks of the breasts were co-registered with 3-D ultrasound image stacks, suggesting for the first time that PAVI, based on the intrinsic tissue contrast, can visualize tissue interfaces other than those with blood, including the inner skin surface and connective tissue sheets. With the designed system, PAVI revealed satisfactory imaging depth and sensitivity for coverage of the entire breast when imaged from both sides in the mammographic geometry with mild compression. PMID:23972486

Xie, Zhixing; Hooi, Fong Ming; Fowlkes, J Brian; Pinsky, Renee W.; Wang, Xueding; Carson, Paul L.

2013-01-01

216

Triple negative tumors accumulate significantly less methylglyoxal specific adducts than other human breast cancer subtypes  

PubMed Central

Metabolic syndrome and type 2 diabetes are associated with increased risk of breast cancer development and progression. Methylglyoxal (MG), a glycolysis by-product, is generated through a non-enzymatic reaction from triose-phosphate intermediates. This dicarbonyl compound is highly reactive and contributes to the accumulation of advanced glycation end products. In this study, we analyzed the accumulation of Arg-pyrimidine, a MG-arginine adduct, in human breast adenocarcinoma and we observed a consistent increase of Arg-pyrimidine in cancer cells when compared with the non-tumoral counterpart. Further immunohistochemical comparative analysis of breast cancer subtypes revealed that triple negative lesions exhibited low accumulation of Arg-pyrimidine compared with other subtypes. Interestingly, the activity of glyoxalase 1 (Glo-1), an enzyme that detoxifies MG, was significantly higher in triple negative than in other subtype lesions, suggesting that these aggressive tumors are able to develop an efficient response against dicarbonyl stress. Using breast cancer cell lines, we substantiated these clinical observations by showing that, in contrast to triple positive, triple negative cells induced Glo-1 expression and activity in response to MG treatment. This is the first report that Arg-pyrimidine adduct accumulation is a consistent event in human breast cancer with a differential detection between triple negative and other breast cancer subtypes. PMID:24978626

Durieux, Florence; Bianchi, Elettra; Turtoi, Andrei; Peulen, Olivier; Peixoto, Paul; Irigaray, Philippe; Uchida, Koji; Belpomme, Dominique; Delvenne, Philippe; Castronovo, Vincent; Bellahcene, Akeila

2014-01-01

217

Knocking down gene expression for growth hormone-releasing hormone inhibits proliferation of human cancer cell lines  

Microsoft Academic Search

Splice Variant 1 (SV-1) of growth hormone-releasing hormone (GHRH) receptor, found in a wide range of human cancers and established human cancer cell lines, is a functional receptor with ligand-dependent and independent activity. In the present study, we demonstrated by western blots the presence of the SV1 of GHRH receptor and the production of GHRH in MDA-MB-468, MDA-MB-435S and T47D

N Barabutis; A V Schally

2008-01-01

218

Precancerous model of human breast epithelial cells induced by NNK for prevention.  

PubMed

Epidemiological investigations have suggested that exposure to tobacco and environmental carcinogens increase the risk of developing human breast cancer. In light of the chronic exposure of human breast tissues to tobacco and environmental carcinogens, we have taken an approach of analyzing cellular changes of immortalized non-cancerous human breast epithelial MCF10A cells during the acquisition of cancerous properties induced by repeated exposure to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) at a low concentration of 100 pM. We found that accumulated exposures of MCF10A cells to NNK result in progressive development of cellular carcinogenesis from a stage of immortalization to precancerous sub-stages of acquiring a reduced dependence on growth factors and acquiring anchorage-independent growth. Using Matrigel for MCF10A cells to form size-restricted acini, we detected that exposures to NNK resulted in altered acinar conformation. Analysis of gene expression profiles by cDNA microarrays revealed up- and down-regulated genes associated with NNK-induced carcinogenesis. Using this cellular carcinogenesis model as a target system to identify anticancer agents, we detected that grape seed proanthocyanadin extract significantly suppressed NNK-induced carcinogenesis of MCF10A cells. Our studies provide a carcinogenesis-cellular model mimicking the accumulative exposure to carcinogens in the progression of human breast epithelial cells to increasingly acquire cancerous properties, as likely occurs in the development of precancerous human breast cells. Our cellular model also serves as a cost-efficient, in vitro system to identify preventive agents that inhibit human breast cell carcinogenesis induced by chronic exposures to carcinogens. PMID:17653854

Siriwardhana, Nalin; Choudhary, Shambhunath; Wang, Hwa-Chain Robert

2008-06-01

219

Identification of breast cancer patients based on human signaling network motifs  

PubMed Central

Identifying breast cancer patients is crucial to the clinical diagnosis and therapy for this disease. Conventional gene-based methods for breast cancer diagnosis ignore gene-gene interactions and thus may lead to loss of power. In this study, we proposed a novel method to select classification features, called “Selection of Significant Expression-Correlation Differential Motifs” (SSECDM). This method applied a network motif-based approach, combining a human signaling network and high-throughput gene expression data to distinguish breast cancer samples from normal samples. Our method has higher classification performance and better classification accuracy stability than the mutual information (MI) method or the individual gene sets method. It may become a useful tool for identifying and treating patients with breast cancer and other cancers, thus contributing to clinical diagnosis and therapy for these diseases. PMID:24284521

Chen, Lina; Qu, Xiaoli; Cao, Mushui; Zhou, Yanyan; Li, Wan; Liang, Binhua; Li, Weiguo; He, Weiming; Feng, Chenchen; Jia, Xu; He, Yuehan

2013-01-01

220

[Menstrual blood and human milk. Reflections and new proposals on breast-feeding in ancient Greece].  

PubMed

Within a larger study on breast-feeding in ancient Greece, we dwelt on four subjects (the superstitions concerning menstrual blood, milk and dairy products consumption by the Athenians, different kinds of milk and beliefs related to the transmission of hereditary characteristics through human milk, the connection between milk, breast and madness) on which we have identified a certain number of neglected sources. Starting from these, we can gain not only some mosaic tiles of the overall fragmentary view on habits and beliefs about breast-feeding, but also, more generally, helpful hints on some aspects of the Greek world and mentality that we barely know. In attempting to reach some general conclusions, we have also considered the iconographic sources, trying to explain, in part at least, the reason for the almost complete absence of scenes of breast-feeding in the archaic and classical art. PMID:24527558

Pedrucci, Giulia

2013-01-01

221

Cell turnover in the "resting" human breast: influence of parity, contraceptive pill, age and laterality.  

PubMed Central

Morphological identification of cell multiplication (mitosis) and cell deletion (apoptosis) within the lobules of the "resting" human breast is used to assess the response of the breast parenchyma to the menstrual cycle. The responses are shown to have a biorhythm in phase with the menstrual cycle, with a 3-day separation of the mitotic and apoptotic peaks. The study fails to demonstrate significant differences in the responses between groups defined according to parity, contraceptive-pill use or presence of fibroadenoma. However, significant differences are found in the apoptotic response according to age and laterality. The results highlight the complexity of modulating influences on breast parenchymal turnover in the "resting" state, and prompt the investigation of other factors as well as steroid hormones and prolactin in the promotion of mitosis. The factors promoting apoptosis in the breast are still not clear. PMID:7126427

Anderson, T. J.; Ferguson, D. J.; Raab, G. M.

1982-01-01

222

Cell turnover in the "resting" human breast: influence of parity, contraceptive pill, age and laterality.  

PubMed

Morphological identification of cell multiplication (mitosis) and cell deletion (apoptosis) within the lobules of the "resting" human breast is used to assess the response of the breast parenchyma to the menstrual cycle. The responses are shown to have a biorhythm in phase with the menstrual cycle, with a 3-day separation of the mitotic and apoptotic peaks. The study fails to demonstrate significant differences in the responses between groups defined according to parity, contraceptive-pill use or presence of fibroadenoma. However, significant differences are found in the apoptotic response according to age and laterality. The results highlight the complexity of modulating influences on breast parenchymal turnover in the "resting" state, and prompt the investigation of other factors as well as steroid hormones and prolactin in the promotion of mitosis. The factors promoting apoptosis in the breast are still not clear. PMID:7126427

Anderson, T J; Ferguson, D J; Raab, G M

1982-09-01

223

Dickkopf-1 mediated tumor suppression in human breast carcinoma cells.  

PubMed

Dickkopf-1 (DKK-1) is a secreted inhibitor of the Wnt signaling pathway. We previously identified DKK-1 as a candidate tumor suppressor and demonstrated that ectopic expression of the DKK-1 suppressed the tumorigenicity of HeLa cells in vitro and in vivo. Since suppression of tumorigenicity of HeLa cells by DKK-1 overexpression was not mediated by effects on beta-catenin dependent transcription, we hypothesized that DKK-1 might also inhibit tumorigenicity of breast carcinoma cell lines lacking an activated canonical Wnt pathway. In the present study we show that ectopic expression of DKK-1 in various breast cancer cell lines resulted in a change in the cell phenotype, increased sensitivity to apoptosis, inhibition of anchorage independent growth in vitro, and suppression of tumorigenicity in vivo. Consistent with known effects of DKK-1 on the canonical Wnt signaling pathway, ectopic expression of DKK-1 in breast carcinoma cells was associated with increased phosphorylation and degradation of beta-catenin. However, none of the breast tumor cells used in this study showed detectable levels of beta-catenin dependent activation of TCF/Lef promoter activity measured by reporter constructs. Consistent with the results of these transient transfection assays, we were unable to demonstrate the expected beta-catenin dependent, TCF/Lef mediated inhibition of cyclin D1 and c-myc gene transcription in breast cells overexpressing DKK-1. However, we found that cells with DKK-1 overexpression have increased activity of CamKII pathway. Overexpression of the constitutively active form of CamKII (T286D) resulted in inhibition of breast cancer cell tumorigenicity. Thus, our study supports the hypothesis that DKK-1 mediated tumor suppressor effect is independent of beta-catenin dependent transcription and identified the CamKII pathway that contributes into DKK-1 signaling. PMID:18157634

Mikheev, Andrei M; Mikheeva, Svetlana A; Maxwell, John-Patrick; Rivo, Julia V; Rostomily, Robert; Swisshelm, Karen; Zarbl, Helmut

2008-11-01

224

Induction of apoptosis in human breast cancer cells by a pulsed atmospheric pressure plasma jet  

NASA Astrophysics Data System (ADS)

By using an atmospheric pressure plasma jet driven by pulsed dc voltage with repetition rate of several tens of kilohertz, we were able to induce apoptosis in cultured human breast cancer cells (MCF-7). The apoptotic changes in cells with plasma treatment were detected by flow cytometry and fluorescence staining assay. A significant portion of these cells was observed to exhibit the apoptotic fragmentation. Helium plasma with additive O2 gas was found to be effective in the induction of apoptosis. This plasma jet provides an effective mode of human breast cancer cell therapy.

Kim, Sun Ja; Chung, T. H.; Bae, S. H.; Leem, S. H.

2010-07-01

225

Antiestrogenic activities of alternate-substituted polychlorinated dibenzofurans in MCF7 human breast cancer cells  

Microsoft Academic Search

Purpose: 1,3,6,8-Substituted alkyl polychlorinated dibenzofurans (PCDFs), typified by 6-methyl-1,3,8-triCDF (MCDF), inhibit 17?-estradiol\\u000a (E2)-induced responses in the rodent uterus and human breast cancer cells. The major purpose of the experiments reported here\\u000a was to determine the structure-dependent antiestrogenic activities of several alternate-substituted (1,3,6,8- and 2,4,6,8-)\\u000a PCDFs. Methods: The antiestrogenic activities were determined in MCF-7 human breast cancer cells using two assays,

Gulan Sun; Stephen Safe

1997-01-01

226

Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ.  

PubMed

Cyclooxygenase-2 (COX-2) is an inducible enzyme that converts arachidonic acid to prostaglandins. Overexpression of the COX-2 gene in mammary glands of transgenic mice was sufficient to induce tumorigenesis. We analyzed COX-2 expression in human breast cancers (and breast cancer cell lines) and adjacent ductal carcinoma in situ (DCIS) as well as its association with HER2/neu and clinicopathological variables. Archival primary breast carcinomas (n = 57), adjacent DCIS (n = 14) and DCIS alone (n = 2) were analyzed for COX-2 and HER2 expression by immunohistochemistry using specific monoclonal antibodies. An immunohistochemical scoring system was used. HER2 gene amplification had been analyzed previously by fluorescence in situ hybridization (n = 20). Histology of carcinomas included infiltrating ductal (n = 44), lobular (n = 2), and other (n = 7). Frozen breast cancers and adjacent normal tissue pairs (n = 9) were analyzed for COX-2 mRNA by reverse transcription-PCR. COX-2 and HER2 expression were also analyzed in human breast cancer cell lines (MCF-7, MCF-7/HER2, SK-BR-3, and MDA-MB-231) by immunoblotting. Cytoplasmic COX-2 expression was detected at an intermediate or high level in epithelial cells in 18 of 42 (43%) invasive breast cancers and in 10 of 16 (63%) cases of DCIS. Normal-appearing breast epithelia adjacent to cancer expressed COX-2 in 81% of cases and was generally focal and of similar or decreased intensity relative to adjacent neoplastic epithelia. COX-2 mRNA was detected in all samples analyzed by reverse transcription-PCR and was increased in eight of nine breast cancers relative to paired normal tissue. In archival tumors, no significant correlation was found between COX-2 and HER2 expression/amplification and clinicopathological variables. COX-2 expression was induced in MCF-7 cells stably transfected with HER2, in contrast to parental MCF-7 cells, and was detected in MDA-MB-231, but not SK-BR-3 cells. COX-2 is frequently overexpressed in invasive breast cancers and in adjacent DCIS and, thus, may be an early event in mammary tumorigenesis. Forced HER2 expression in MCF-7 cells was shown to up-regulate COX-2, although no association was found in human tumors. Our results suggest that nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors may be useful in the chemoprevention and therapy of human breast cancer. PMID:11912139

Half, Elizabeth; Tang, Xi Ming; Gwyn, Karin; Sahin, Aysegul; Wathen, Kyle; Sinicrope, Frank A

2002-03-15

227

Expression and DNA methylation changes in human breast epithelial cells after bisphenol A (BPA) exposure  

PubMed Central

It has been suggested that xenoestrogens, a group of agents termed endocrine disruptors, may contribute to the development of hormone-dependent cancers such as breast and endometrial cancers. We previously demonstrated that the xenoestrogen bisphenol A (BPA) was able to induce transformation in vitro of human breast epithelial cells. The normal-like human breast epithelial cells MCF-10F form tubules in collagen (3-D cultures) although, after treatment with BPA (10-5M and 10-6M BPA), the cells produced less tubules (73% and 80%, respectively) and some spherical masses (27% and 20%, respectively). In the present work, expression and DNA methylation analyses were performed in these cells after being exposure to BPA. These cells showed an increased expression of BRCA1, BRCA2, BARD1, CtIP, RAD51, and BRCC3, all genes involved in DNA repair, and down-regulation of PDCD5 and BCL2L11 (BIM), both involved in apoptosis. Furthermore, DNA methylation analysis shown that BPA exposure induced hypermethylation of BCL2L11, PARD6G, FOXP1, and SFRS11, and hypomethylation of NUP98 and CtIP (RBBP8). Our results indicated that normal human breast epithelial cells exposed to BPA increased the expression of genes involved in DNA repair in order to overcome the DNA damage induced by this chemical. These results suggest that the breast tissue of women with BRCA1 or BRCA2 mutations could be more susceptible to be transformed by BPA. PMID:22576693

Fernandez, Sandra V.; Huang, Yong; Snider, Kara E.; Zhou, Yan; Pogash, Thomas J.; Russo, Jose

2012-01-01

228

Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors  

SciTech Connect

Highlights: •CAFs in human breast and ovarian tumors express pro-inflammatory factors. •Expression of pro-inflammatory factors correlates with tumor invasiveness. •Expression of pro-inflammatory factors is associated with NF-?b activation in CAFs. -- Abstract: Inflammation has been established in recent years as a hallmark of cancer. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. We previously demonstrated that CAFs also mediate tumor-enhancing inflammation in a mouse model of skin carcinoma. Breast and ovarian carcinomas are amongst the leading causes of cancer-related mortality in women and cancer-related inflammation is linked with both these tumor types. However, the role of CAFs in mediating inflammation in these malignancies remains obscure. Here we show that CAFs in human breast and ovarian tumors express high levels of the pro-inflammatory factors IL-6, COX-2 and CXCL1, previously identified to be part of a CAF pro-inflammatory gene signature. Moreover, we show that both pro-inflammatory signaling by CAFs and leukocyte infiltration of tumors are enhanced in invasive ductal carcinoma as compared with ductal carcinoma in situ. The pro-inflammatory genes expressed by CAFs are known NF-?B targets and we show that NF-?B is up-regulated in breast and ovarian CAFs. Our data imply that CAFs mediate tumor-promoting inflammation in human breast and ovarian tumors and thus may be an attractive target for stromal-directed therapeutics.

Erez, Neta, E-mail: netaerez@post.tau.ac.il [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel)] [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Glanz, Sarah [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel)] [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Raz, Yael [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel) [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Department of Obstetrics and Gynecology, LIS Maternity Hospital, Tel Aviv Sourasky Medical Center, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Avivi, Camilla [Department of Pathology, Sheba Medical Center, Tel Hashomer, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel)] [Department of Pathology, Sheba Medical Center, Tel Hashomer, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Barshack, Iris [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel) [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Department of Pathology, Sheba Medical Center, Tel Hashomer, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel)

2013-08-02

229

Hard X-ray Microscopic Imaging Of Human Breast Tissues  

SciTech Connect

X-ray microscopy with synchrotron radiation will be a useful tool for innovation of x-ray imaging in clinical and laboratory settings. It helps us observe detailed internal structure of material samples non-invasively in air. And, it also has the potential to solve some tough problems of conventional breast imaging if it could evaluate various conditions of breast tissue effectively. A new hard x-ray microscope with a spatial resolution better than 100 nm was installed at Pohang Light Source, a third generation synchrotron radiation facility in Pohang, Korea. The x-ray energy was set at 6.95 keV, and the x-ray beam was monochromatized by W/B4C monochromator. Condenser and objective zone plates were used as x-ray lenses. Zernike phase plate next to condenser zone plate was introduced for improved contrast imaging. The image of a sample was magnified 30 times by objective zone plate and 20 times by microscope objective, respectively. After additional 10 times digital magnification, the total magnifying power was up to 6000 times in the end. Phase contrast synchrotron images of 10-{mu}m-thick female breast tissue of the normal, fibroadenoma, fibrocystic change and carcinoma cases were obtained. By phase contrast imaging, hard x-rays enable us to observe many structures of breast tissue without sample preparations such as staining or fixation.

Park, Sung H.; Kim, Hong T.; Kim, Jong K. [College of Medicine, Catholic University of Daegu, 3056-6 Daemyung-Dong, Nam-Gu, Daegu 705-718 (Korea, Republic of); Jheon, Sang H. [College of Medicine, Seoul National University, 27 Youngun-Dong, Jongro-Gu, Seoul 110-799 (Korea, Republic of); Youn, Hwa S. [Pohang Accelerator Laboratory, Pohang University of Science and Technology, 31 San, Hyoja-dong, Pohang, KyungBuk 790-784 (Korea, Republic of)

2007-01-19

230

A genomic analysis of mouse models of breast cancer reveals molecular features of mouse models and relationships to human breast cancer  

PubMed Central

Introduction Genomic variability limits the efficacy of breast cancer therapy. To simplify the study of the molecular complexity of breast cancer, researchers have used mouse mammary tumor models. However, the degree to which mouse models model human breast cancer and are reflective of the human heterogeneity has yet to be demonstrated with gene expression studies on a large scale. Methods To this end, we have built a database consisting of 1,172 mouse mammary tumor samples from 26 different major oncogenic mouse mammary tumor models. Results In this dataset we identified heterogeneity within mouse models and noted a surprising amount of interrelatedness between models, despite differences in the tumor initiating oncogene. Making comparisons between models, we identified differentially expressed genes with alteration correlating with initiating events in each model. Using annotation tools, we identified transcription factors with a high likelihood of activity within these models. Gene signatures predicted activation of major cell signaling pathways in each model, predictions that correlated with previous genetic studies. Finally, we noted relationships between mouse models and human breast cancer at both the level of gene expression and predicted signal pathway activity. Importantly, we identified individual mouse models that recapitulate human breast cancer heterogeneity at the level of gene expression. Conclusions This work underscores the importance of fully characterizing mouse tumor biology at molecular, histological and genomic levels before a valid comparison to human breast cancer may be drawn and provides an important bioinformatic resource. PMID:25069779

2014-01-01

231

Loss of pigment epithelium-derived factor: a novel mechanism for the development of endocrine resistance in breast cancer  

PubMed Central

Introduction Despite the benefits of endocrine therapies such as tamoxifen and aromatase inhibitors in treating estrogen receptor (ER) alpha-positive breast cancer, many tumors eventually become resistant. The molecular mechanisms governing resistance remain largely unknown. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein that displays broad anti-tumor activity based on dual targeting of the tumor microenvironment (anti-angiogenic action) and the tumor cells (direct anti-tumor action). Recent studies indicate that PEDF expression is significantly reduced in several tumor types, including breast cancer, and that its reduction is associated with disease progression and poor patient outcome. In the current study, we investigated the role of PEDF in the development of endocrine resistance in breast cancer. Methods PEDF mRNA and protein levels were measured in several endocrine-resistant breast cancer cell lines including MCF-7:5C, MCF-7:2A, and BT474 and in endocrine-sensitive cell lines MCF-7, T47D, and ZR-75-1 using real-time PCR and western blot analyses. Tissue microarray analysis and immunohistochemistry were used to assess the PEDF protein level in tamoxifen-resistant breast tumors versus primary tumors. Lentiviruses were used to stably express PEDF in endocrine-resistant breast cancer cell lines to determine their sensitivity to tamoxifen following PEDF re-expression. Results We found that PEDF mRNA and protein levels were dramatically reduced in endocrine-resistant MCF-7:5C, MCF-7:2A, and BT474 breast cancer cells compared with endocrine-sensitive MCF-7, T47D, and ZR-75-1 cells, and that loss of PEDF was associated with enhanced expression of pSer167ER? and the receptor tyrosine kinase rearranged during transfection (RET). Importantly, we found that silencing endogenous PEDF in tamoxifen-sensitive MCF-7 and T47D breast cancer cells conferred tamoxifen resistance whereas re-expression of PEDF in endocrine-resistant MCF-7:5C and MCF-7:2A cells restored their sensitivity to tamoxifen in vitro and in vivo through suppression of RET. Lastly, tissue microarray studies revealed that PEDF protein was reduced in ~52.4% of recurrence tumors (31 out of 59 samples) and loss of PEDF was associated with disease progression and poor patient outcome. Conclusion Overall, these findings suggest that PEDF silencing might be a novel mechanism for the development of endocrine resistance in breast cancer and that PEDF expression might be a predictive marker of endocrine sensitivity. PMID:23151593

2012-01-01

232

DNA synthesis of benign human breast tumors in the untreated athymic "nude" mouse. An in vivo model to study hormonal influences on growth of human breast tissues.  

PubMed

DNA synthesis in 33 human benign breast tissue biopsy specimens (HBT) was determined by 3H-thymidine radioautography 0, 15, 30, and 60 days after s.c. transplantation to female nude mice. A third of the grafts was removed from each mouse at each time period. Grafts and 0-day slices were exposed to 3H-thymidine in vitro. Labeling indices (LI) [number of radiolabeled epithelial cells per unit area epithelium (0.1 mm2)] were calculated for 0-day slices and grafts from each mouse at each time period. The LI of high 0-day HBT grafts (LI greater than 15) decreased significantly between 0 and 15 and 0 and 30 days. The LI of low 0-day HBT grafts (LI less than 15) increased significantly at 15 days then decreased to 0-day levels at 30 days. No significant differences in LI of HBT grafts were observed between 30 and 60 days. Thus, a model has been proposed for studies of factors effecting the growth of human breast tissues transplanted to nude mice in which (1) each mouse is used as its own control by measuring DNA synthesis of grafts before and after treatment, and (2) the treatment is initiated 30 days or more after transplantation of breast tissues when graft DNA synthesis is stabilized. Using this model, we have observed marked increases in HBT graft DNA snythesis induced by human placental lactogen treatment of host nude mice from day 42 to day 60 after HBT transplantation. PMID:7370957

McManus, M J; Welsch, C W

1980-04-15

233

Quantitative determination of the human breast milk macronutrients by near-infrared Raman spectroscopy  

NASA Astrophysics Data System (ADS)

This work proposes the evaluation of the macronutrient constitution of human breast milk based on the spectral information provided by near-infrared Raman spectroscopy. Human breast milk (5 mL) from a subject was collected during the first two weeks of breastfeeding and stocked in -20°C freezer. Raman spectra were measured using a Raman spectrometer (830 nm excitation) coupled to a fiber based Raman probe. Spectra of human milk were dominated by bands of proteins, lipids and carbohydrates in the 600-1800 cm-1 spectral region. Raman spectroscopy revealed differences in the biochemical constitution of human milk depending on the time of breastfeeding startup. This technique could be employed to develop a classification routine for the milk in Human Milk Banking (HMB) depending on the nutritional facts.

Motta, Edlene d. C. M.; Zângaro, Renato A.; Silveira, Landulfo, Jr.

2012-03-01

234

Plasma Membrane Proteomics of Human Breast Cancer Cell Lines Identifies Potential Targets for Breast Cancer Diagnosis and Treatment  

PubMed Central

The use of broad spectrum chemotherapeutic agents to treat breast cancer results in substantial and debilitating side effects, necessitating the development of targeted therapies to limit tumor proliferation and prevent metastasis. In recent years, the list of approved targeted therapies has expanded, and it includes both monoclonal antibodies and small molecule inhibitors that interfere with key proteins involved in the uncontrolled growth and migration of cancer cells. The targeting of plasma membrane proteins has been most successful to date, and this is reflected in the large representation of these proteins as targets of newer therapies. In view of these facts, experiments were designed to investigate the plasma membrane proteome of a variety of human breast cancer cell lines representing hormone-responsive, ErbB2 over-expressing and triple negative cell types, as well as a benign control. Plasma membranes were isolated by using an aqueous two-phase system, and the resulting proteins were subjected to mass spectrometry analysis. Overall, each of the cell lines expressed some unique proteins, and a number of proteins were expressed in multiple cell lines, but in patterns that did not always follow traditional clinical definitions of breast cancer type. From our data, it can be deduced that most cancer cells possess multiple strategies to promote uncontrolled growth, reflected in aberrant expression of tyrosine kinases, cellular adhesion molecules, and structural proteins. Our data set provides a very rich and complex picture of plasma membrane proteins present on breast cancer cells, and the sorting and categorizing of this data provides interesting insights into the biology, classification, and potential treatment of this prevalent and debilitating disease. PMID:25029196

Ziegler, Yvonne S.; Moresco, James J.; Tu, Patricia G.; Yates, John R.; Nardulli, Ann M.

2014-01-01

235

Profiles of Caspase Activation and Gene Expression in Human Breast Cancer Cell Line MCF7, after Cyclophosphamide, Doxorubicin, 5Fluorouracil (CDF) Multi-Drug Administration  

Microsoft Academic Search

The multidrug treatment, CDF (cyclophos- phamide (CPA), doxorubicin (DXR), and 5- fluorouracil (5-FU)), is a common chemotherapy protocol for breast cancer. However, the molecular mechanisms underlying its toxicity for breast cancer cells remain unclear. As a laboratory model of breast cancer chemotherapy, the human breast cancer cell line MCF-7 was treated with CDF or the individual CDF reagents. Western blotting

Fumihiko Kugawa; Akemichi Ueno

2010-01-01

236

Rapid spread of mouse mammary tumor virus in cultured human breast cells  

PubMed Central

Background The role of mouse mammary tumor virus (MMTV) as a causative agent in human breast carcinogenesis has recently been the subject of renewed interest. The proposed model is based on the detection of MMTV sequences in human breast cancer but not in healthy breast tissue. One of the main drawbacks to this model, however, was that until now human cells had not been demonstrated to sustain productive MMTV infection. Results Here, we show for the first time the rapid spread of mouse mammary tumor virus, MMTV(GR), in cultured human mammary cells (Hs578T), ultimately leading to the infection of every cell in culture. The replication of the virus was monitored by quantitative PCR, quantitative RT-PCR and immunofluorescence imaging. The infected human cells expressed, upon cultivation with dexamethasone, MMTV structural proteins and released spiked B-type virions, the infectivity of which could be neutralized by anti-MMTV antibody. Replication of the virus was efficiently blocked by an inhibitor of reverse transcription, 3'-azido-3'-deoxythymidine. The human origin of the infected cells was confirmed by determining a number of integration sites hosting the provirus, which were unequivocally identified as human sequences. Conclusion Taken together, our results show that human cells can support replication of mouse mammary tumor virus. PMID:17931409

Indik, Stanislav; Günzburg, Walter H; Kulich, Pavel; Salmons, Brian; Rouault, Francoise

2007-01-01

237

Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors  

PubMed Central

Purpose Accumulating evidence supports the existence of breast cancer stem cells (BCSCs), which are characterized by their capacity to self-renew and divide indefinitely, and resistance to conventional therapies. The Notch pathway is important for stem cell renewal, and is a potential target for BCSC-directed therapy. Experimental Design Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in advanced breast cancer patients, designed to determine the maximally tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies. Results Treatment with GSI reduced BCSCs in MC1 and BMC-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically meaningful doses of both drugs were possible, with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44+/CD24?, ALDH+, and MSFE were observed in tumors of patients undergoing serial biopsies. Conclusions These preclinical data demonstrate that pharmacological inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial demonstrates feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer. PMID:23340294

Schott, Anne F.; Landis, Melissa D.; Dontu, Gabriela; Griffith, Kent A.; Layman, Rachel M.; Krop, Ian; Paskett, Lacey A; Wong, Helen; Dobrolecki, Lacey E.; Froehlich, Amber M.; Paranilam, Jaya; Hayes, Daniel F.; Wicha, Max S.; Chang, Jenny C.

2013-01-01

238

SHP2 expression is an independent negative prognostic factor in human breast cancer  

PubMed Central

Aims Src-homology-phosphotyrosyl-phosphatase 2 (SHP2) is a ubiquitously expressed phosphatase that plays an essential role in the downstream signaling pathways of multiple growth factor receptors, thus representing a potential target for cancer therapy. Recent studies suggest that SHP2 contributes to tumor initiation, progression and metastasis in breast cancer, yet the impact of SHP2 expression on prognosis in human breast cancer has not been evaluated. Methods and Results To further explore the role of SHP2 in breast cancer, we conducted an immunohistochemical study on a tissue microarray encompassing 1401 formalin-fixed breast cancer specimens with detailed clinical annotation and outcomes data. 651 of 1401 (46%) evaluable breast cancers were positive for SHP2. SHP2 expression was positively associated with tumor grade, lymph node status, and tumor stage. In univariate survival analysis, cases with SHP2 expression had a significantly worse overall survival (OS). In multivariate analysis, SHP2 remained an independent negative prognostic factor for OS. SHP2 expression was a negative prognostic factor for OS in the luminal A and the luminal B HER2? intrinsic subtypes. Conclusions Our data demonstrate for the first time that SHP2 is an independent predictor of survival in breast cancer, suggesting that SHP2 may be a potential target for therapy. PMID:23672411

Muenst, S; Obermann, EC; Gao, F; Oertli, D; Viehl, CT; Weber, WP; Fleming, T; Gillanders, WE; Soysal, SD

2013-01-01

239

Dicer-Mediated Upregulation of BCRP Confers Tamoxifen Resistance in Human Breast Cancer Cells  

PubMed Central

Purpose Tamoxifen (Tam) is the most prescribed hormonal agent for treatment of estrogen receptor ?-positive breast cancer patients. Using microarray analysis, we observed that metastatic breast tumors resistant to Tam therapy had elevated levels of Dicer. Experimental Design We overexpressed Dicer in ER?-positive MCF-7 human breast cancer cells, and observed a concomitant increase in expression of the breast cancer resistance protein BCRP. We thus hypothesized that Tam resistance associated with Dicer overexpression in ER?-positive breast cancer cells may involve BCRP. We analyzed BCRP function in Dicer-overexpressing cells using growth in soft agar and mammosphere formation, and evaluated intracellular Tam efflux. Results In the presence of Tam, Dicer-overexpressing cells formed resistant colonies in soft agar, and treatment with BCRP inhibitors restored Tam sensitivity. Tumor xenograft studies confirmed that Dicer-overexpressing cells were resistant to Tam in vivo. Tumors and distant metastases could be initiated with as few as 5 mammosphere cells from both vector and Dicer-overexpressing cells, indicating that the mammosphere assay selected for cells with enhanced tumor initiating and metastatic capacity. Dicer-overexpressing cells with elevated levels of BCRP, effluxed Tam more efficiently than control cells, and BCRP inhibitors were able to inhibit efflux. Conclusion Dicer-overexpressing breast cancer cells enriched for cells with enhanced BCRP function. We hypothesize that it is this population which may be involved in the emergence of Tam-resistant growth. BCRP may be a novel clinical target to restore Tam sensitivity. PMID:21878538

Selever, Jennifer; Gu, Guowei; Lewis, Michael T.; Beyer, Amanda; Herynk, Matthew H.; Covington, Kyle R.; Tsimelzon, Anna; Dontu, Gabriela; Provost, Patrick; Di Pietro, Attilio; Boumendjel, Ahcene; Albain, Kathy; Miele, Lucio; Weiss, Heidi; Barone, Ines; Ando, Sebastiano; Fuqua, Suzanne A. W.

2012-01-01

240

Decreased expression of C10orf10 and its prognostic significance in human breast cancer.  

PubMed

Breast cancer is a common malignant tumor, which severely threatens the health of women with an increasing incidence in many countries. Here, we identified C10orf10 as a novel differentially expression gene using expression microarray screening. The expression analysis indicated that C10orf10 was frequently decreased in human breast cancers compared to noncancerous breast tissues (81/95, P = 0.0063). Kaplan-Meier analysis indicated that patients with low C10orf10 expression showed a poorer prognosis both in mRNA (n = 1115, P = 0.0013) and protein (n = 100, P = 0.003) levels. Univariate and multivariate analysis showed that the C10orf10 expression was an independent prognostic factor for overall survival of breast cancer patients. Further analysis revealed that low expression of C10orf10 was an unfavorable factor for the prognosis of the patients who were luminal A, luminal B, Her2+ subtypes, at histological grade 2, lymph node negative and ER positive. Our data provided the first evidence that C10orf10 expression was frequently decreased in breast cancer tissues, and low expression of C10orf10 may be an important prognostic factor for poorer survival time of breast cancer patients. PMID:24936657

Deng, Junjiang; Dong, Yan; Li, Chong; Zuo, Wenwei; Meng, Gang; Xu, Chengping; Li, Jianjun

2014-01-01

241

Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin ?1  

PubMed Central

Introduction We have previously reported that induction of epidermal growth factor receptor and ErbB2 in response to antihormonal agents may provide an early mechanism to allow breast cancer cells to evade the growth-inhibitory action of such therapies and ultimately drive resistant cell growth. More recently, the other two members of the ErbB receptor family, ErbB3 and ErbB4, have been implicated in antihormone resistance in breast cancer. In the present study, we have investigated whether induction of ErbB3 and/or ErbB4 may provide an alternative resistance mechanism to antihormonal action in a panel of four oestrogen receptor (ER)-positive breast cancer cell lines. Methods MCF-7, T47D, BT474 and MDAMB361 cell lines were exposed to fulvestrant (100 nM) for seven days, and effects on ErbB3/4 expression and signalling, as well as on cell growth, were assessed. Effects of heregulin ?1 (HRG?1) were also examined in the absence and presence of fulvestrant to determine the impact of ER blockade on the capacity of this ErbB3/4 ligand to promote signalling and cell proliferation. Results Fulvestrant potently reduced ER expression and transcriptional activity and significantly inhibited growth in MCF-7, T47D, BT474 and MDAMB361 cells. However, alongside this inhibitory activity, fulvestrant also consistently induced protein expression and activity of ErbB3 in MCF-7 and T47D cells and ErbB4 in BT474 and MDAMB361 cell lines. Consequently, fulvestrant treatment sensitised all cell lines to the actions of the ErbB3/4 ligand HRG?1 with enhanced ErbB3/4-driven signalling activity, reexpression of cyclin D1 and significant increases in cell proliferation being observed when compared to untreated cells. Indeed, in T47D and MDAMB361 HRG?1 was converted from a ligand having negligible or suppressive growth activity into one that potently promoted cell proliferation. Consequently, fulvestrant-mediated growth inhibition was completely overridden by HRG?1 in all four cell lines. Conclusions These findings suggest that although antihormones such as fulvestrant may have potent acute growth-inhibitory activity in ER-positive breast cancer cells, their ability to induce and sensitise cells to growth factors may serve to reduce and ultimately limit their inhibitory activity. PMID:21396094

2011-01-01

242

Transforming growth factor-? signalling controls human breast cancer metastasis in a zebrafish xenograft model  

PubMed Central

Introduction The transforming growth factor beta (TGF-?) signalling pathway is known to control human breast cancer invasion and metastasis. We demonstrate that the zebrafish xenograft assay is a robust and dependable animal model for examining the role of pharmacological modulators and genetic perturbation of TGF-? signalling in human breast tumour cells. Methods We injected cancer cells into the embryonic circulation (duct of cuvier) and examined their invasion and metastasis into the avascular collagenous tail. Various aspects of the TGF-? signalling pathway were blocked by chemical inhibition, small interfering RNA (siRNA), or small hairpin RNA (shRNA). Analysis was conducted using fluorescent microscopy. Results Breast cancer cells with different levels of malignancy, according to in vitro and in vivo mouse studies, demonstrated invasive and metastatic properties within the embryonic zebrafish model that nicely correlated with their differential tumourigenicity in mouse models. Interestingly, MCF10A M2 and M4 cells invaded into the caudal hematopoietic tissue and were visible as a cluster of cells, whereas MDA MB 231 cells invaded into the tail fin and were visible as individual cells. Pharmacological inhibition with TGF-? receptor kinase inhibitors or tumour specific Smad4 knockdown disturbed invasion and metastasis in the zebrafish xenograft model and closely mimicked the results we obtained with these cells in a mouse metastasis model. Inhibition of matrix metallo proteinases, which are induced by TGF-? in breast cancer cells, blocked invasion and metastasis of breast cancer cells. Conclusions The zebrafish-embryonic breast cancer xenograft model is applicable for the mechanistic understanding, screening and development of anti-TGF-? drugs for the treatment of metastatic breast cancer in a timely and cost-effective manner. PMID:24196484

2013-01-01

243

Regulated expression patterns of IRX-2 , an Iroquois-class homeobox gene, in the human breast  

Microsoft Academic Search

In the mouse mammary gland, homeobox gene expression patterns suggest roles in development and neoplasia. In the human breast, we now identify a family of Iroquois-class (IRX) homeobox genes. One gene, IRX-2, is expressed in discrete epithelial cell lineages being found in ductal and lobular epithelium, but not in myoepithelium. Expression is absent from associated mesenchymal adipose stroma. During gland

Michael T. Lewis; Sarajane Ross; Phyllis A. Strickland; C. John Snyder; Charles W. Daniel

1999-01-01

244

Analysis of polypeptide expression in benign and malignant human breast lesions: down-regulation of cytokeratins  

Microsoft Academic Search

Malignant progression of tumour cells is caused by the accumulation of genetic defects, which when combined will generate a large phenotypic diversity. Simultaneous quantitation of a large number of gene products in tumour cells is desirable, but difficult to achieve. We have here quantitated the levels of a number of abundant polypeptides in human breast carcinoma cells using two-dimensional gel

B Franzén; S Linder; AA Alaiya; E Eriksson; K Uruy; T Hirano; K Okuzawa; G Auer

1996-01-01

245

Proteomics reveals protein profile changes in doxorubicin – treated MCF7 human breast cancer cells  

Microsoft Academic Search

MCF-7 cells are extensively used as a cell model to investigate human breast tumors and the cellular mechanism of antitumor drugs such as doxorubicin (DOX), an anthracycline antitumor drug widely used in clinical chemotherapy. To understand the effects of DOX on the protein expression, we perform a comprehensive proteomics to survey global changes in proteins after DOX treatment in MCF-7

Shui-Tein Chen; Tai-Long Pan; Ya-Chi Tsai; Chun-Ming Huang

2002-01-01

246

Scanning Electrochemical Microscopy: Detection of Human Breast Cancer Cells by Redox Environment  

Microsoft Academic Search

Scanning electrochemical microscopy (SECM) can be used to measure the redox activity of individual human breast cells. A chemical mediator (e.g. quinone) that rapidly crosses the membrane participates in intracellular redox reactions that are recorded on a microsecond timescale by an ultramicroelectrode positioned close to the membrane. Measurements of redox reactivity yield rate constants that are different for cancerous and

Susan A. Rotenberg; Michael V. Mirkin

2004-01-01

247

Rap1 Integrates Tissue Polarity, Lumen Formation, and Tumorigenic Potential in Human Breast Epithelial Cells  

E-print Network

Rap1 Integrates Tissue Polarity, Lumen Formation, and Tumorigenic Potential in Human Breast disrupt tissue architecture and initiate tumor formation. Here, we show that the small GTPase Rap1 is a crucial element in organizing acinar structure and inducing lumen formation. Rap1 activity in malignant

Nelson, Celeste M.

248

Reduced telomere DNA content is correlated with genomic instability and metastasis in invasive human breast carcinoma  

Microsoft Academic Search

Telomere shortening leads to genomic instability and has been correlated with poor outcome in several types of cancer. A recently described, robust titration assay was used to quantify telomere DNA content in frozen and paraffin-embedded specimens of 49 invasive human breast carcinomas, including tumors with normal or abnormal contents of genomic DNA, which produced regional, distant, or local disease. Telomere

Jeffrey K. Griffith; Jennifer E. Bryant; Colleen A. Fordyce; Frank D. Gilliland; Nancy E. Joste; Robert K. Moyzis

1999-01-01

249

Anti-cancer effects of Kochia scoparia fruit in human breast cancer cells  

PubMed Central

Background: The fruit of Kochia scoparia Scharder is widely used as a medicinal ingredient for the treatment of dysuria and skin diseases in China, Japan and Korea. Especially, K. scoparia had been used for breast masses and chest and flank pain. Objective: To investigate the anti-cancer effect of K. scoparia on breast cancer. Materials and Methods: We investigated the anti-cancer effects of K. scoparia, methanol extract (MEKS) in vitro. We examined the effects of MEKS on the proliferation rate, cell cycle arrest, reactive oxygen species (ROS) generation and activation of apoptosis-associated proteins in MDA-MB-231, human breast cancer cells. Results: MTT assay results demonstrated that MEKS decreased the proliferation rates of MDA-MB-231 cells in a dose-dependent manner with an IC50 value of 36.2 ?g/ml. MEKS at 25 ?g/ml significantly increased the sub-G1 DNA contents of MDA-MB-231 cells to 44.7%, versus untreated cells. In addition, MEKS induced apoptosis by increasing the levels of apoptosis-associated proteins such as cleaved caspase 3, cleaved caspase 8, cleaved caspase 9 and cleaved Poly (ADP-ribose) polymerase (PARP). Conclusion: These results suggest that MEKS inhibits cell proliferation and induces apoptosis in breast cancer cells and that MEKS may have potential chemotherapeutic value for the treatment of human breast cancer.

Han, Hye-Yeon; Kim, Hyungwoo; Son, Yong Hae; Lee, Guemsan; Jeong, Sung-Hee; Ryu, Mi Heon

2014-01-01

250

Androgen Receptor Overexpression Induces Tamoxifen Resistance in Human Breast Cancer Cells  

PubMed Central

Although the androgen receptor (AR) is a known clinical target in prostate cancer, little is known about its possible role in breast cancer. We have investigated the role of AR expression in human breast cancer in response to treatment with the antiestrogen tamoxifen. Resistance to tamoxifen is a major problem in treating women with breast cancer. By gene expression profiling, we found elevated AR, and reduced estrogen receptor (ER) ? mRNA in tamoxifen-resistant tumors. Exogenous overexpression of AR rendered ER?-positive MCF-7 breast cancer cells resistant to the growth-inhibitory effects of tamoxifen in anchorage-independent growth assays, and in xenograft studies in athymic nude mice. AR-overexpressing cells remained sensitive to growth stimulation with dihydrotestosterone. Treatment with the AR antagonist Casodex™ (bicalutamide) reversed this resistance, demonstrating the involvement of AR signaling in tamoxifen resistance. In AR-overexpressing cells, tamoxifen induced transcriptional activation by ER? that could be blocked by Casodex, suggesting that AR overexpression enhances tamoxifen’s agonistic properties. Our data suggest a role for AR overexpression as a novel mechanism of hormone resistance, so that AR may offer a new clinical therapeutic target in human breast cancers. PMID:19533338

De Amicis, Francesca; Thirugnansampanthan, Janagi; Cui, Yukun; Selever, Jennifer; Beyer, Amanda; Parra, Irma; Weigel, Nancy L.; Herynk, Matthew H.; Tsimelzon, Anna; Lewis, Michael T.; Chamness, Gary C.; Hilsenbeck, Susan G.; Ando, Sebastiano; Fuqua, Suzanne A. W.

2010-01-01

251

Quantitative risk assessment of human salmonellosis in Canadian broiler chicken breast from retail to consumption.  

PubMed

The current quantitative risk assessment model followed the framework proposed by the Codex Alimentarius to provide an estimate of the risk of human salmonellosis due to consumption of chicken breasts which were bought from Canadian retail stores and prepared in Canadian domestic kitchens. The model simulated the level of Salmonella contamination on chicken breasts throughout the retail-to-table pathway. The model used Canadian input parameter values, where available, to represent risk of salmonellosis. From retail until consumption, changes in the concentration of Salmonella on each chicken breast were modeled using equations for growth and inactivation. The model predicted an average of 318 cases of salmonellosis per 100,000 consumers per year. Potential reasons for this overestimation were discussed. A sensitivity analysis showed that concentration of Salmonella on chicken breasts at retail and food hygienic practices in private kitchens such as cross-contamination due to not washing cutting boards (or utensils) and hands after handling raw meat along with inadequate cooking contributed most significantly to the risk of human salmonellosis. The outcome from this model emphasizes that responsibility for protection from Salmonella hazard on chicken breasts is a shared responsibility. Data needed for a comprehensive Canadian Salmonella risk assessment were identified for future research. PMID:22616714

Smadi, Hanan; Sargeant, Jan M

2013-02-01

252

Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells.  

PubMed

Although the androgen receptor (AR) is a known clinical target in prostate cancer, little is known about its possible role in breast cancer. We have investigated the role of AR expression in human breast cancer in response to treatment with the antiestrogen tamoxifen. Resistance to tamoxifen is a major problem in treating women with breast cancer. By gene expression profiling, we found elevated AR and reduced estrogen receptor (ER) alpha mRNA in tamoxifen-resistant tumors. Exogenous overexpression of AR rendered ERalpha-positive MCF-7 breast cancer cells resistant to the growth-inhibitory effects of tamoxifen in anchorage-independent growth assays and in xenograft studies in athymic nude mice. AR-overexpressing cells remained sensitive to growth stimulation with dihydrotestosterone. Treatment with the AR antagonist Casodex (bicalutamide) reversed this resistance, demonstrating the involvement of AR signaling in tamoxifen resistance. In AR-overexpressing cells, tamoxifen induced transcriptional activation by ERalpha that could be blocked by Casodex, suggesting that AR overexpression enhances tamoxifen's agonistic properties. Our data suggest a role for AR overexpression as a novel mechanism of hormone resistance, so that AR may offer a new clinical therapeutic target in human breast cancers. PMID:19533338

De Amicis, Francesca; Thirugnansampanthan, Janagi; Cui, Yukun; Selever, Jennifer; Beyer, Amanda; Parra, Irma; Weigel, Nancy L; Herynk, Matthew H; Tsimelzon, Anna; Lewis, Michael T; Chamness, Gary C; Hilsenbeck, Susan G; Andò, Sebastiano; Fuqua, Suzanne A W

2010-05-01

253

Cyclopamine inhibition of human breast cancer cell growth independent of Smoothened (Smo).  

PubMed

Altered hedgehog signaling is implicated in the development of approximately 20-25% of all cancers, especially those of soft tissues. Genetic evidence in mice as well as immunolocalization studies in human breast cancer specimens suggest that deregulated hedgehog signaling may contribute to breast cancer development. Indeed, two recent studies demonstrated that anchorage-dependent growth of some human breast cancer cell lines is impaired by cyclopamine, a potent hedgehog signaling antagonist targeting the Smoothened (SMO) protein. However, specificity of cyclopamine at the dosage required for growth inhibition (> or =10 microM) remained an open question. In this paper we demonstrate that hedgehog signaling antagonists, including cyclopamine, and a second compound, CUR0199691, can inhibit growth of estrogen receptor (ER)-positive and ER-negative tumorigenic breast cancer cells at elevated doses. However, our results indicate that, for most breast cancer cell lines, growth inhibition by these compounds can be independent of detectable Smo gene expression. Rather, our results suggest that cyclopamine and CUR0199691 have unique secondary molecular targets at the dosages required for growth inhibition that are unrelated to hedgehog signaling. PMID:18563554

Zhang, Xiaomei; Harrington, Nikesha; Moraes, Ricardo C; Wu, Meng-Fen; Hilsenbeck, Susan G; Lewis, Michael T

2009-06-01

254

High-risk human papillomavirus (HPV) DNA sequences in metaplastic breast carcinomas of Mexican women  

PubMed Central

Background Metaplastic carcinoma, an uncommon subtype of breast cancer, is part of the spectrum of basal-like, triple receptor-negative breast carcinomas. The present study examined 20 surgical specimens of metaplastic breast carcinomas, for the presence of high-risk Human papillomavirus (HPV), which is suspected to be a potential carcinogenic agent for breast carcinoma. Methods Mastectomy specimens from patients harboring metaplastic breast carcinoma, as defined by the World Health Organization (WHO), and who attended the Instituto Nacional de Cancerologia in Mexico City, were retrieved from the files of the Department of Pathology accumulated during a 16-year period (1995–2008). Demographic and clinical information was obtained from patients’ medical records. DNA was extracted from formalin-fixed, paraffin-embedded tumors and HPV type-specific amplification was performed by means of Polymerase chain reaction (PCR). Quantitative Real-time (RT) PCR was conducted in HPV positive cases. Statistically, the association of continuous or categorical variables with HPV status was tested by the Student t, the Chi square, or Fisher’s exact tests, as appropriate. Results High-risk HPV DNA was detected in eight (40%) of 20 metaplastic breast carcinomas: seven (87.5%) HPV-16 and one (12.5%) HPV-18. Mean age of patients with HPV-positive cases was 49 years (range 24–72 years), the same as for HPV-negative cases (range, 30–73 years). There were not striking differences between HPV?+?and HPV– metaplastic carcinomas regarding clinical findings. Nearly all cases were negative for estrogen, progesterone and Human epidermal growth factor receptor 2 (HER2), but positive for Epidermal growth factor receptor (EGFR). Conclusions High-risk HPV has been strongly associated with conventional breast carcinomas, although the subtle mechanism of neoplastic transformation is poorly understood. In Mexican patients, the prevalence of HPV infection among metaplastic breast carcinomas is higher than in non-metaplastic ones, as so the HPV viral loads; notwithstanding, HPV viral loads show wide variation and remain even lower than cervical and other non-cervical carcinomas, making it difficult to assume that HPV could play a key role in breast carcinogenesis. Further studies are warranted to elucidate the meaning of the presence of high-risk HPVDNA in breast carcinomas. PMID:24083491

2013-01-01

255

Correlation between extent of osteolytic damage and metastatic burden of human breast cancer metastasis in nude mice: Real-time PCR quantitation  

Microsoft Academic Search

Orthotopic or intracardiac injection of human breast cancer cell lines into immunocompromised mice allows study of the molecular\\u000a basis of breast cancer metastasis. We have established a quantitative real-time PCR approach to analyze metastatic spread\\u000a of human breast cancer cells inoculated into nude mice via these routes. We employed MDA-MB-231 human breast cancer cells\\u000a genetically tagged with a bacterial ?-galactosidase

Angus M. Tester; Julie A. Sharp; Nirada Dhanesuan; Mark Waltham; Erik W. Thompson

2002-01-01

256

Estradiol and progesterone receptors in human breast fibroadenomas.  

PubMed

Estradiol and progesterone receptors (ER and PR) were studied in 46 breast fibroadenomas obtained at different periods of the menstrual cycle (n = 38) or from patients under combined estrogen-progestagen contraceptive (n = 4) or substitutive progestagen treatment for progesterone insufficiency (n = 4). Cytosolic and nuclear ER (ERc and ERn) increased throughout the follicular phase and were at their maximal level in the preovulatory phase. They decreased during the luteal phase. PR levels were high in the follicular phase, especially in the cytosol (PRc). PRc then decreased while nuclear progesterone receptor (PRn) increased at the beginning of the luteal phase. Thereafter, PRc and PRn decreased and remained low during the luteal phase. PRc and PRn levels in fibroadenomas from patients under estrogen-progestagen therapy were similar to those found during the luteal phase of untreated patients. In patients receiving a substitutive progestagen treatment to correct progesterone insufficiency, PRn was markedly higher than PRc. The existence of ER and PR in breast fibroadenomas and the variations in their levels during the menstrual cycle or under hormonal treatment provide valuable information on the hormone dependency of breast fibroadenoma. PMID:7229001

Kuttenn, F; Fournier, S; Durand, J C; Mauvais-Jarvis, P

1981-06-01

257

DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines  

PubMed Central

Background DNA hypermethylation events and other epimutations occur in many neoplasms, producing gene expression changes that contribute to neoplastic transformation, tumorigenesis, and tumor behavior. Some human cancers exhibit a hypermethylator phenotype, characterized by concurrent DNA methylation-dependent silencing of multiple genes. To determine if a hypermethylation defect occurs in breast cancer, the expression profile and promoter methylation status of methylation-sensitive genes were evaluated among breast cancer cell lines. Results The relationship between gene expression (assessed by RT-PCR and quantitative real-time PCR), promoter methylation (assessed by methylation-specific PCR, bisulfite sequencing, and 5-aza-2'deoxycytidine treatment), and the DNA methyltransferase machinery (total DNMT activity and expression of DNMT1, DNMT3a, and DNMT3b proteins) were examined in 12 breast cancer cell lines. Unsupervised cluster analysis of the expression of 64 methylation-sensitive genes revealed two groups of cell lines that possess distinct methylation signatures: (i) hypermethylator cell lines, and (ii) low-frequency methylator cell lines. The hypermethylator cell lines are characterized by high rates of concurrent methylation of six genes (CDH1, CEACAM6, CST6, ESR1, LCN2, SCNN1A), whereas the low-frequency methylator cell lines do not methylate these genes. Hypermethylator cell lines coordinately overexpress total DNMT activity and DNMT3b protein levels compared to normal breast epithelial cells. In contrast, most low-frequency methylator cell lines possess DNMT activity and protein levels that are indistinguishable from normal. Microarray data mining identified a strong cluster of primary breast tumors that express the hypermethylation signature defined by CDH1, CEACAM6, CST6, ESR1, LCN2, and SCNN1A. This subset of breast cancers represents 18/88 (20%) tumors in the dataset analyzed, and 100% of these tumors were classified as basal-like, suggesting that the hypermethylator defect cosegregates with poor prognosis breast cancers. Conclusion These observations combine to strongly suggest that: (a) a subset of breast cancer cell lines express a hypermethylator phenotype, (b) the hypermethylation defect in these breast cancer cell lines is related to aberrant overexpression of DNMT activity, (c) overexpression of DNMT3b protein significantly contributes to the elevated DNMT activity observed in tumor cells expressing this phenotype, and (d) the six-gene hypermethylator signature characterized in breast cancer cell lines defines a distinct cluster of primary basal-like breast cancers. PMID:18221536

Roll, J Devon; Rivenbark, Ashley G; Jones, Wendell D; Coleman, William B

2008-01-01

258

Association of autotaxin and lysophosphatidic acid receptor 3 with aggressiveness of human breast carcinoma.  

PubMed

In vitro and in vivo experimental studies have demonstrated the role of lysophosphatidic acid (LPA) signaling in tumor proliferation, invasiveness, and metastasis. Among LPA receptors, the overexpression of LPA receptor 3 (LPAR3) in transgenic mice has resulted in the highest rate of breast cancer metastasis. Our goal is to evaluate the LPA-producing enzyme autotaxin and LPAR3 as potential therapeutic targets in breast cancer patients. The expression of autotaxin and LPAR3 was examined by immunohistochemical analysis of 87 invasive human breast carcinomas. Carcinomas were more frequently positive for autotaxin and LPAR3 (24.4 and 43 %, respectively) compared to adjacent normal breast tissue (6.1 and 2.9 %, respectively). Increased stromal autotaxin expression was found in 16.3 % of the tumors. LPAR3 overexpression was associated with less differentiated tumors, human epidermal growth factor receptor 2 expression, and absence of progesterone receptors. The luminal type A carcinomas showed the lowest frequency of autotaxin and LPAR3 expression. Strong desmoplastic stromal reaction was more frequent among the carcinomas with autotaxin-positive tumor cells or autotaxin-positive stroma. Patients with carcinomas overexpressing LPAR3 in epithelial cells or autotaxin in stromal cells were more likely to have larger tumors, nodal involvement, and higher stage disease. Autotaxin overexpression in tumor cells also correlated with tumor size and clinical stage. Our data indicate that the increased expression of LPAR3 and autotaxin in human breast cancer is associated with tumor aggressiveness. They also suggest that LPA mediates tumor metastatic ability and peritumoral desmoplastic reaction through autocrine-paracrine mechanisms. A substantial portion of breast cancer patients might benefit from autotoxin/LPA receptor-targeted therapies. PMID:22922883

Popnikolov, Nikolay K; Dalwadi, Bela H; Thomas, Jeff D; Johannes, Gregg J; Imagawa, Walter T

2012-12-01

259

Determination of olanzapine in human breast milk by high-performance liquid chromatography with electrochemical detection  

Microsoft Academic Search

A reversed-phase high-performance liquid chromatographic–electrochemical assay was developed and validated for the quantification of olanzapine in human breast milk. The assay involved a solid-phase extraction (SPE) of olanzapine and its internal standard on a Bond Elut Certify LRC mixed-mode cartridge. After conditioning of the SPE cartridge, human milk (1 ml) was passed through the cartridge. The cartridge was washed with

Stephen C Kasper; Edward L Mattiuz; Steven P Swanson; Jenting Andre Chiu; Jason T Johnson; Carlos O Garner

1999-01-01

260

Human antimicrobial protein hCAP18\\/LL37 promotes a metastatic phenotype in breast cancer  

Microsoft Academic Search

INTRODUCTION: Human cathelicidin antimicrobial protein, hCAP18, and its C-terminal peptide LL-37 is a multifunctional protein. In addition to being important in antimicrobial defense, it induces chemotaxis, stimulates angiogenesis and promotes tissue repair. We previously showed that human breast cancer cells express high amounts of hCAP18, and hypothesised that hCAP18\\/LL-37 may be involved in tumour progression. METHODS: hCAP18 mRNA was quantified

Günther Weber; Clara Ibel Chamorro; Fredrik Granath; Annelie Liljegren; Sami Zreika; Zuzana Saidak; Bengt Sandstedt; Samuel Rotstein; Romuald Mentaverri; Fabio Sánchez; Andor Pivarcsi; Mona Ståhle

2009-01-01

261

Characterization of SWI/SNF protein expression in human breast cancer cell lines and other malignancies.  

PubMed

Organization of genomic DNA into chromatin aids in the regulation of gene expression by limiting access to transcriptional machinery. The SWI/SNF family of complexes, which are conserved from yeast to humans, are ATP-dependent chromatin-remodeling enzymes required for the transcription of a number of genes in yeast. In humans, the gene encoding the BAF47/hSNF5 subunit of the complex, located at 22q11.2, has been found to be mutated in a number of human tumors including rhabdoid, rhabdomyosarcoma, chronic myeloid leukemia, and CNS tumors such as medulloblastomas and choroid plexus carcinomas. In addition, loss of heterozygosity (LOH) has been reported for the BAF47 region in breast and liver cancer. LOH has also been reported in breast and ovarian cancer within 17q12-25, a gene-rich area including BRCA1, BAF60B, and BAF57. Interestingly, the gene encoding the BAF155/hSWI3 subunit of the complex maps to 3p21-p23, an area of chromosomal deletion seen in a number of human adenocarcinomas including breast, kidney, pancreas, and ovary. To look for abnormalities in these proteins as well as the SWI/SNF complex in general, we have determined the protein status of core human SWI/SNF components BAF170, BAF155, BAF57, BAF53a, and BAF47 in 21 breast cell lines. The complex status in other human tumor cell lines of various tissue types was also examined. We also determined the protein status of the human SWI2 homologues, hBRM/SWI2alpha and BRG1/SWI2beta as well as two other proteins found in human SWI/SNF complexes, BAF180 and BAF250. In this study, we identified the first cell line negative for the BAF57 protein as well as a pancreatic carcinoma cell line negative for both the BRG-1 and hBRM proteins. PMID:11147808

Decristofaro, M F; Betz, B L; Rorie, C J; Reisman, D N; Wang, W; Weissman, B E

2001-01-01

262

The \\/753-binding Protein MDM2 Gene Is Differentially Expressed in Human Breast Carcinoma1  

Microsoft Academic Search

The human p53-binding protein murine double minute 2 (MDM2) is believed to function as a negative regulator of p53. The MDM2 gene was cloned and sequenced only recently and was found to be amplified in a variety of sarcomas. Although mutations in thep5J gene have been shown to occur in human breast carcinoma (HBC), no information is available on MDM2

M. Saeed Sheikh; Zhi-Ming Shao; Aril Hussain; Joseph A. Fontana

1993-01-01

263

Identification of differentially expressed microRNAs in human male breast cancer  

Microsoft Academic Search

BACKGROUND: The discovery of small non-coding RNAs and the subsequent analysis of microRNA expression patterns in human cancer specimens have provided completely new insights into cancer biology. Genetic and epigenetic data indicate oncogenic or tumor suppressor function of these pleiotropic regulators. Therefore, many studies analyzed the expression and function of microRNA in human breast cancer, the most frequent malignancy in

Ulrich Lehmann; Thomas Streichert; Benjamin Otto; Cord Albat; Britta Hasemeier; Henriette Christgen; Elisa Schipper; Ursula Hille; Hans H Kreipe; Florian Länger

2010-01-01

264

RhoC Upregulation Is Correlated with Reduced E-cadherin in Human Breast Cancer Specimens After Chemotherapy and in Human Breast Cancer MCF-7 Cells.  

PubMed

Therapy-resistant cancer cells are a major problem in cancer research. Recent studies suggest that the epithelial-mesenchymal transition (EMT) is a key mechanism in therapy resistance. Yet, the expressions of EMT markers, EMT core regulators, and a stem cell marker of BMI1 during chemotherapy have been poorly analyzed in clinical breast cancer specimens. In the present study, we investigated the roles of RhoC under chemotherapy to follow up on earlier findings demonstrating the involvement of RhoC in prostate cancer resistance to endocrine therapy. Immunohistochemically, E-cadherin expression was significantly lower in human breast cancer specimens analyzed after chemotherapy than specimens biopsied before chemotherapy. Significant upregulation of fibronectin, a mesenchymal EMT marker, was found in post-chemotherapy analysis. A study of the EMT core regulators of SNAIL1, SNAIL2, TWIST1, and a well-known stem cell marker of BMI1 revealed no post-chemotherapy upregulation of these molecules. In contrast, RhoC expression was significantly upregulated in post-chemotherapy breast cancer specimens. MCF-7 cells stably transfected with the constitutive active (CA) RhoC plasmid manifested a reduced level of E-cadherin at the peripheries and disorganization of actin fibers, with no accompanying upregulation of SNAIL1, SNAIL2, TWIST1, or BMI1 in Western blots. Exposure of etoposide on MCF-7 cells showed RhoC upregulation together with reduced membranous expression of E-cadherin and disorganization of actin fibers. In MTT assay, however, the CA-RhoC-expressing MCF-7 cells failed to show chemotherapy resistance under etoposide treatment. Taken in sum, RhoC may contribute to an EMT-like process in human breast cancer during chemotherapy. PMID:25123151

Kawata, Hirotoshi; Kamiakito, Tomoko; Omoto, Yawara; Miyazaki, Chieko; Hozumi, Yasuo; Tanaka, Akira

2014-12-01

265

Amide Proton Transfer Imaging of the Human Breast at 7 Tesla: Development and Reproducibility  

PubMed Central

Chemical exchange saturation transfer (CEST) can offer information about protons associated with mobile proteins through the amide proton transfer (APT) effect, which has been shown to discriminate tumor from healthy tissue and, more recently, has been suggested as a prognosticator of response to therapy. Despite this promise, APT effects are small (only a few percent of the total signal); and APT imaging is often prone to artifacts resulting from system instability. Here we present a procedure that enables the detection of APT effects in the human breast at 7 T while mitigating these issues. Adequate signal-to-noise ratio (SNR) was achieved via an optimized quadrature RF breast coil and 3D acquisitions. To reduce the influence of fat, effective fat suppression schemes were developed that did not degrade SNR. To reduce the levels of ghosting artifacts, dummy scans have been integrated into the scanning protocol. Compared to results obtained at 3 T, the standard deviation of the measured APT effect was reduced by a factor of four at 7 T, allowing for the detection of APT effects with a standard deviation of 1% in the human breast at 7 T. Together, these results demonstrate that the APT effect can be reliably detected in the healthy human breast with a high level of precision at 7 T. PMID:23559550

Klomp, Dennis W. J.; Dula, Adrienne N.; Arlinghaus, Lori R.; Italiaander, Michel; Dortch, Richard D.; Zu, Zhongliang; Williams, Jason M.; Gochberg, Daniel F.; Luijten, Peter R.; Gore, John C.; Yankeelov, Thomas E.; Smith, Seth A.

2013-01-01

266

Agonists and antagonists of GnRH-I and -II reduce metastasis formation by triple-negative human breast cancer cells in vivo  

Microsoft Academic Search

Metastasis to bone is a frequent problem of advanced breast cancer. Particularly breast cancers, which do not express estrogen\\u000a and progesterone receptors and which have no overexpression\\/amplification of the HER2-neu gene, so called triple-negative\\u000a breast cancers, are considered as very aggressive and possess a bad prognosis. About 60% of all human breast cancers and about\\u000a 74% of triple-negative breast cancers

Antje Schubert; Thomas Hawighorst; Günter Emons; Carsten Gründker

267

Monoclonal Antibody to HER2\\/neuReceptor Modulates Repair of Radiation induced DNA Damage and Enhances Radiosensitivity of Human Breast Cancer Cells Overexpressing This Oncogene1  

Microsoft Academic Search

The management of human breast cancer frequently includes radiation therapy as an important intervention, and improvement in the clinical efficacy of radiation is desirable. Overexpression of the HER-2 growth factor receptor occurs in 25-30% of human breast cancers and correlates with poor clinical outcome, including earlier local relapse following con- servative surgery accompanied by radiation therapy. In breast cancer cells

Richard J. Pietras; Joseph C. Poen; David Gallardo; P. Nancy Wongvipat; H. Julie Lee; Dennis J. Slamon

1999-01-01

268

Investigations of Functional and Structural Interactions Between c-src and HER2: Involvement in Human Breast Tumor Formation.  

National Technical Information Service (NTIS)

To investigate whether interactions between c-Src and other HER family members may play a role in breast tumor progression, we characterized a panel of thirteen human breast carcinoma cell lines and thirteen tumor samples for expression levels of HER fami...

A. P. Belches, S. J. Parsons

1999-01-01

269

The PDZ protein TIP-1 facilitates cell migration and pulmonary metastasis of human invasive breast cancer cells in athymic mice  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer This study has revealed novel oncogenic functions of TIP-1 in human invasive breast cancer. Black-Right-Pointing-Pointer Elevated TIP-1 expression levels in human breast cancers correlate to the disease prognosis. Black-Right-Pointing-Pointer TIP-1 knockdown suppressed the cell migration and pulmonary metastasis of human breast cancer cells. Black-Right-Pointing-Pointer TIP-1 knockdown suppressed the expression and functionality of motility-related genes. -- Abstract: Tax-interacting protein 1 (TIP-1, also known as Tax1bp3) inhibited proliferation of colon cancer cells through antagonizing the transcriptional activity of beta-catenin. However, in this study, elevated TIP-1 expression levels were detected in human invasive breast cancers. Studies with two human invasive breast cancer cell lines indicated that RNAi-mediated TIP-1 knockdown suppressed the cell adhesion, proliferation, migration and invasion in vitro, and inhibited tumor growth in mammary fat pads and pulmonary metastasis in athymic mice. Biochemical studies showed that TIP-1 knockdown had moderate and differential effects on the beta-catenin-regulated gene expression, but remarkably down regulated the genes for cell adhesion and motility in breast cancer cells. The decreased expression of integrins and paxillin was accompanied with reduced cell adhesion and focal adhesion formation on fibronectin-coated surface. In conclusion, this study revealed a novel oncogenic function of TIP-1 suggesting that TIP-1 holds potential as a prognostic biomarker and a therapeutic target in the treatment of human invasive breast cancers.

Han, Miaojun [Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Yunnan (China) [Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Yunnan (China); Graduate School, Chinese Academy of Sciences, Beijing (China); Department of Radiation Oncology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States); Wang, Hailun [Department of Radiation Oncology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States)] [Department of Radiation Oncology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States); Zhang, Hua-Tang [Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Yunnan (China)] [Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Yunnan (China); Han, Zhaozhong, E-mail: zhaozhong.han@vanderbilt.edu [Department of Radiation Oncology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States) [Department of Radiation Oncology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States); Department of Cancer Biology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States); Vanderbilt-Ingram Cancer Center, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States)

2012-05-25

270

Localization of human breast tumors grafted in nude mice with a monoclonal antibody directed against a defined cell surface antigen of human mammary epithelial cells  

Microsoft Academic Search

Summary A mouse monoclonal antibody (BLMRL-HMFG-Mc5) prepared against a defined cell surface antigen of human mammary epithelial cells, non-penetrating glycoprotein (NPGP), was used in imaging and distribution studies in athymic nude mice grafted with human breast tumors. Forin vivo tissue distribution studies,125I-labeled monoclonal antibody was injected into nude mice carrying simulated metastases of human tumors (breast and colon carcinomas). After

Roberto L. Ceriani; Masao Sasaki; Douglas Orthendahl; Leon Kaufman

1988-01-01

271

Anticancer Effects of Different Seaweeds on Human Colon and Breast Cancers  

PubMed Central

Seafoods and seaweeds represent some of the most important reservoirs of new therapeutic compounds for humans. Seaweed has been shown to have several biological activities, including anticancer activity. This review focuses on colorectal and breast cancers, which are major causes of cancer-related mortality in men and women. It also describes various compounds extracted from a range of seaweeds that have been shown to eradicate or slow the progression of cancer. Fucoidan extracted from the brown algae Fucus spp. has shown activity against both colorectal and breast cancers. Furthermore, we review the mechanisms through which these compounds can induce apoptosis in vitro and in vivo. By considering the ability of compounds present in seaweeds to act against colorectal and breast cancers, this review highlights the potential use of seaweeds as anticancer agents. PMID:25255129

Moussavou, Ghislain; Kwak, Dong Hoon; Obiang-Obonou, Brice Wilfried; Ogandaga Maranguy, Cyr Abel; Dinzouna-Boutamba, Sylvatrie-Danne; Lee, Dae Hoon; Manvoudou Pissibanganga, Ordelia Gwenaelle; Ko, Kisung; Seo, Jae In; Choo, Young Kug

2014-01-01

272

Anticancer effects of different seaweeds on human colon and breast cancers.  

PubMed

Seafoods and seaweeds represent some of the most important reservoirs of new therapeutic compounds for humans. Seaweed has been shown to have several biological activities, including anticancer activity. This review focuses on colorectal and breast cancers, which are major causes of cancer-related mortality in men and women. It also describes various compounds extracted from a range of seaweeds that have been shown to eradicate or slow the progression of cancer. Fucoidan extracted from the brown algae Fucus spp. has shown activity against both colorectal and breast cancers. Furthermore, we review the mechanisms through which these compounds can induce apoptosis in vitro and in vivo. By considering the ability of compounds present in seaweeds to act against colorectal and breast cancers, this review highlights the potential use of seaweeds as anticancer agents. PMID:25255129

Moussavou, Ghislain; Kwak, Dong Hoon; Obiang-Obonou, Brice Wilfried; Maranguy, Cyr Abel Ogandaga; Dinzouna-Boutamba, Sylvatrie-Danne; Lee, Dae Hoon; Pissibanganga, Ordelia Gwenaelle Manvoudou; Ko, Kisung; Seo, Jae In; Choo, Young Kug

2014-09-01

273

Antitumor efficacy of piperine in the treatment of human HER2-overexpressing breast cancer cells.  

PubMed

Piperine is a bioactive component of black pepper, Piper nigrum Linn, commonly used for daily consumption and in traditional medicine. Here, the molecular mechanisms by which piperine exerts antitumor effects in HER2-overexpressing breast cancer cells was investigated. The results showed that piperine strongly inhibited proliferation and induced apoptosis through caspase-3 activation and PARP cleavage. Furthermore, piperine inhibited HER2 gene expression at the transcriptional level. Blockade of ERK1/2 signaling by piperine significantly reduced SREBP-1 and FAS expression. Piperine strongly suppressed EGF-induced MMP-9 expression through inhibition of AP-1 and NF-?B activation by interfering with ERK1/2, p38 MAPK, and Akt signaling pathways resulting in a reduction in migration. Finally, piperine pretreatment enhanced sensitization to paclitaxel killing in HER2-overexpressing breast cancer cells. Our findings suggest that piperine may be a potential agent for the prevention and treatment of human breast cancer with HER2 overexpression. PMID:23870999

Do, Minh Truong; Kim, Hyung Gyun; Choi, Jae Ho; Khanal, Tilak; Park, Bong Hwan; Tran, Thu Phuong; Jeong, Tae Cheon; Jeong, Hye Gwang

2013-12-01

274

Scanning electrochemical microscopy of living cells: Different redox activities of nonmetastatic and metastatic human breast cells  

PubMed Central

Electrochemical methods have been widely used to monitor physiologically important molecules in biological systems. This report describes the first application of the scanning electrochemical microscope (SECM) to probe the redox activity of individual living cells. The possibilities of measuring the rate and investigating the pathway of transmembrane charge transfer are demonstrated. By this approach, significant differences are detected in the redox responses given by nonmotile, nontransformed human breast epithelial cells, breast cells with a high level of motility (engendered by overexpression of protein kinase C?), and highly metastatic breast cancer cells. SECM analysis of the three cell lines reveals reproducible differences with respect to the kinetics of charge transfer by several redox mediators. PMID:10963658

Liu, Biao; Rotenberg, Susan A.; Mirkin, Michael V.

2000-01-01

275

The triterpenoid Cucurbitacin B augments the anti-proliferative activity of chemotherapy in human breast cancer  

PubMed Central

Despite recent advances in therapy, breast cancer remains the second most common cause of death from malignancy in women. Chemotherapy plays a major role in breast cancer management, and combining chemotherapeutic agents with non-chemotherapeutic agents is of considerable clinical interest. Cucurbitacins are triterpenes compounds found in plants of the Cucurbitaceae family, reported to have anti-cancer and anti-inflamatory activities. Previously, we have shown antiproliferative activity of cucurbitacin B (CuB) in breast cancer, and we hypothesized that combining CuB with chemotherapeutic agents can augment their anti-tumor effect. Here, we show that a combination of CuB with either docetaxel (DOC) or gemcitabine (GEM) synergistically inhibited the proliferation of MDA-MB-231 breast cancer cells in vitro. This antiproliferative effect was accompanied by an increase in apoptosis rates. Furthermore, in vivo treatment of human breast cancer orthotopic xenografts in immunodeficient mice with CuB at either low (0.5 mg/kg) or high (1 mg/kg) doses in combination with either DOC (20 mg/kg) or GEM (12.5 mg/kg) significantly reduced tumor volume as compared to monotherapy of each drug. Importantly, no significant toxicity was noted with low dose CuB in combination with either DOC or GEM. In conclusion, combination of CuB at a relatively low concentration with either of the chemotherapeutic agents, DOC or GEM, shows prominent antiproliferative activity against breast cancer cells without increased toxicity. This promising combination should be examined in therapeutic trials of breast cancer. PMID:23165325

Aribi, Ahmed; Gery, Sigal; Lee, Dhong Hyun; Thoennissen, Nils H.; Thoennissen, Gabriela B.; Alvarez, Rocio; Ho, Quoc; Lee, Kunik; Doan, Ngan B.; Chan, Kin T.; Toh, Melvin; Said, Jonathan W.; Koeffler, H. Phillip

2012-01-01

276

Sensitization of human breast cancer cells to natural killer cell-mediated cytotoxicity by proteasome inhibition.  

PubMed

The proteasome inhibitor, bortezomib, has direct anti-tumour effects and has been demonstrated to sensitize tumour cells to tumour necrosis factor-related apoptosis-inducing ligand-mediated apoptosis. Natural killer (NK) cells are effective mediators of anti-tumour responses, both through cytotoxic granule killing and apoptosis-inducing pathways. We therefore investigated if bortezomib sensitized human breast cancer cells to killing by the human NK cell line, NK-92. Bortezomib was unable to sensitize MDA-231 breast cancer cells to NK cell-mediated killing in short-term in vitro assays. However, bortezomib did cause these cells to up-regulate apoptosis-related mRNA as well as death receptors on the cell surface. In a long-term in vitro tumour outgrowth assay that allows NK cells to use their full repertoire of killing pathways, bortezomib sensitized three breast cancer cell lines to NK cell-mediated killing, which led to greater anti-tumour effects than either treatment alone. We then used a xenogeneic mouse model in which CB-17 SCID mice were injected with human breast cancer cells. This model displayed the effectiveness of NK-92 cells, but the addition of bortezomib did not increase the survival further or reduce the number of lung metastases in tumour-bearing mice. However, while bortezomib was highly cytotoxic to NK-92 cells in vitro, bortezomib treatment in vivo did not decrease NK-92 function, suggesting that through alternative dosing or timing of bortezomib, greater efficacy may occur from combined therapy. These data demonstrate that combined treatment of human breast cancer with bortezomib and NK cells has the potential to generate superior anti-tumour responses than either therapy alone. PMID:19220837

Ames, E; Hallett, W H D; Murphy, W J

2009-03-01

277

Recovery of extracellular vesicles from human breast milk is influenced by sample collection and vesicle isolation procedures  

PubMed Central

Extracellular vesicles (EV) in breast milk carry immune relevant proteins and could play an important role in the instruction of the neonatal immune system. To further analyze these EV and to elucidate their function it is important that native populations of EV can be recovered from (stored) breast milk samples in a reproducible fashion. However, the impact of isolation and storage procedures on recovery of breast milk EV has remained underexposed. Here, we aimed to define parameters important for EV recovery from fresh and stored breast milk. To compare various protocols across different donors, breast milk was spiked with a well-defined murine EV population. We found that centrifugation of EV down into density gradients largely improved density-based separation and isolation of EV, compared to floatation up into gradients after high-force pelleting of EV. Using cryo-electron microscopy, we identified different subpopulations of human breast milk EV and a not previously described population of lipid tubules. Additionally, the impact of cold storage on breast milk EV was investigated. We determined that storing unprocessed breast milk at ?80°C or 4°C caused death of cells present in breast milk, leading to contamination of the breast milk EV population with storage-induced EV. Here, an alternative method is proposed to store breast milk samples for EV analysis at later time points. The proposed adaptations to the breast milk storage and EV isolation procedures can be applied for EV-based biomarker profiling of breast milk and functional analysis of the role of breast milk EV in the development of the neonatal immune system. PMID:25206958

Zonneveld, Marijke I.; Brisson, Alain R.; van Herwijnen, Martijn J. C.; Tan, Sisareuth; van de Lest, Chris H. A.; Redegeld, Frank A.; Garssen, Johan; Wauben, Marca H. M.; Nolte-'t Hoen, Esther N. M.

2014-01-01

278

Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells  

PubMed Central

Substantial evidence indicates that exposure to bisphenol A (BPA) during early development may increase breast cancer risk later in life. The changes may persist into puberty and adulthood, suggesting an epigenetic process being imposed in differentiated breast epithelial cells. The molecular mechanisms by which early memory of BPA exposure is imprinted in breast progenitor cells and then passed onto their epithelial progeny are not well understood. The aim of this study was to examine epigenetic changes in breast epithelial cells treated with low-dose BPA. We also investigated the effect of BPA on the ER? signaling pathway and global gene expression profiles. Compared to control cells, nuclear internalization of ER? was observed in epithelial cells preexposed to BPA. We identified 170 genes with similar expression changes in response to BPA. Functional analysis confirms that gene suppression was mediated in part through an ER?-dependent pathway. As a result of exposure to BPA or other estrogen-like chemicals, the expression of lysosomal-associated membrane protein 3 (LAMP3) became epigenetically silenced in breast epithelial cells. Furthermore, increased DNA methylation in the LAMP3 CpG island was this repressive mark preferentially occurred in ER?-positive breast tumors. These results suggest that the in vitro system developed in our laboratory is a valuable tool for exposure studies of BPA and other xenoestrogens in human cells. Individual and geographical differences may contribute to altered patterns of gene expression and DNA methylation in susceptible loci. Combination of our exposure model with epigenetic analysis and other biochemical assays can give insight into the heritable effect of low-dose BPA in human cells. PMID:20678512

Weng, Yu-I; Hsu, Pei-Yin; Liyanarachchi, Sandya; Liu, Joseph; Deatherage, Daniel E.; Huang, Yi-Wen; Zuo, Tao; Rodriguez, Benjamin; Lin, Ching-Hung; Cheng, Ann-Lii; Huang, Tim H.-M.

2010-01-01

279

A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells.  

PubMed

Inhibitor of apoptosis protein (IAP) suppresses apoptosis through binding and inhibiting active caspases-3, -7 and -9 via its baculoviral IAP repeat (BIR) domains. During apoptosis the caspase inhibition by IAPs can be negatively regulated by a mitochondrial protein second mitochondrial-derived activator of caspase (Smac). Smac physically interacts with multiple IAPs and relieves their inhibitory effect on caspases-3, -7 and -9. Recently, a small molecule Smac-mimic compound (Smac-mimic), which potentiates TNF-related apoptosis-inducing ligand (TRAIL) and tumor necrosis factor (TNF)-alpha mediated cell death in glioblastoma T98G cells and HeLa cells, was identified and characterized. To determine the efficacy of this compound in breast cancer cells, we first measured protein expression of three IAPs: XIAP, cIAP-1, and cIAP-2 in nine independent breast cancer cell lines. Three cell lines were chosen: a high IAPs expressing line MDA-MB-231, and two low IAPs expressing lines, T47D and MDA-MB-453. The cell lines were tested for their sensitivity to Smac-mimic alone or in combination with TRAIL or etoposide. Acting alone, Smac-mimic was quite potent with a cytotoxic IC50 of 3.8 nM in high IAPs expressing MDA-MB-231 cells, but was inactive at a much higher concentration in low IAPs expressing T47D and MDA-MB-453 cells. In fact, as low as 2.5 nM of Smac-mimic alone was sufficient to activate caspase-3 and induce apoptosis in MDA-MB-231 cells. In combinational treatments with TRAIL or etoposide, Smac-mimic significantly sensitized cells to growth suppression in MDA-MB-231 cells, but to a lesser extent in T47D and MDA-MB-453 cells. Furthermore, it significantly synergized MDA-MB-231, but not T47D cells to apoptosis induced by either TRAIL or etoposide. Thus, in these cell lines, Smac-mimic acts in an apparent IAPs dependent manner to induce apoptosis alone as well as sensitizes breast cancer cells to TRAIL or etoposide induced apoptosis via caspase-3 activation. PMID:16044155

Bockbrader, Katrina M; Tan, Mingjia; Sun, Yi

2005-11-10

280

Presence and characterization of insulin-like growth factor 1 receptors in human benign breast disease.  

PubMed

Insulin-like growth factor 1 binding sites were characterized in human benign breast disease. We demonstrated the presence of one high affinity binding site. Chemical cross-linking of [125I]IGF1 to benign breast disease membranes in reducing condition and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed one band with an apparent Mr of 130,000. The specificity of the binding was studied: IGF 2 was a good competitor whereas insulin competed for binding with a potency lower than 1/100 that of IGF1. This IGF1 binding corresponded to the previously described type I IGF receptor (IGF1-R). IGF1-R was assayed in 35 cases of benign breast disease and two samples of normal breast tissue. Forty-three per cent of the lesions were IGF1-R positive. The mean geometric level of specific binding was 1.98% in the whole population, it was significantly lower in adenofibromas (1.55%) than in epithelial hyperplasia (2.5%); it was 2% in dystrophic disease. IGF1-R was undetectable in normal tissue. Considering our previous results showing that almost all the breast cancers contained IGF1-R, these data suggest that the increase in IGF1-R could be a marker of malignant tumor development. PMID:2972546

Peyrat, J P; Bonneterre, J; Laurent, J C; Louchez, M M; Amrani, S; Leroy-Martin, B; Vilain, M O; Delobelle, A; Demaille, A

1988-09-01

281

Inappropriate production of collagen and prolyl hydroxylase by human breast cancer cells in vivo.  

PubMed Central

Thirty-two scirrhous cancers of breast have been examined to determine the origin of the collagen stroma in these tumours. Employing two immunohistochemical techniques it has been shown that the malignant epithelial cells in 30 of these tumours contain not only collagen but also prolyl hydroxylase, a key enzyme in collagen biosynthesis. Neither this enzyme nor collagen was detectable in the spindle cells in the stroma of these tumours. Neither the epithelium in normal breast, that in fibrocystic disease and in fibroadenomata, nor the malignant epithelium in two medullary cancers of breast contained either collagen or prolyl hydroxylase. These results strongly suggest that the malignant epithelium of scirrhous breast cancers produces its own collagen stroma and that the scirrhous reaction in these tumours is not a host response to tumour invasion. The production of collagen and prolyl hydroxylase by breast cancer cells (of the scirrhous type) therefore represents another example of inappropriate protein production by a human tumour. Images Fig. 4 Fig. 5 Fig. 1 Fig. 2 Fig. 3 Fig. 6 Fig. 7 PMID:169865

Al-Adnani, M. S.; Kirrane, J. A.; McGee, J. O.

1975-01-01

282

Antitumor activity of colloidal silver on MCF-7 human breast cancer cells  

PubMed Central

Background Colloidal silver has been used as an antimicrobial and disinfectant agent. However, there is scarce information on its antitumor potential. The aim of this study was to determine if colloidal silver had cytotoxic effects on MCF-7 breast cancer cells and its mechanism of cell death. Methods MCF-7 breast cancer cells were treated with colloidal silver (ranged from 1.75 to 17.5 ng/mL) for 5 h at 37°C and 5% CO2 atmosphere. Cell Viability was evaluated by trypan blue exclusion method and the mechanism of cell death through detection of mono-oligonucleosomes using an ELISA kit and TUNEL assay. The production of NO, LDH, and Gpx, SOD, CAT, and Total antioxidant activities were evaluated by colorimetric assays. Results Colloidal silver had dose-dependent cytotoxic effect in MCF-7 breast cancer cells through induction of apoptosis, shown an LD50 (3.5 ng/mL) and LD100 (14 ng/mL) (*P < 0.05), significantly decreased LDH (*P < 0.05) and significantly increased SOD (*P < 0.05) activities. However, the NO production, and Gpx, CAT, and Total antioxidant activities were not affected in MCF-7 breast cancer cells. PBMC were not altered by colloidal silver. Conclusions The present results showed that colloidal silver might be a potential alternative agent for human breast cancer therapy. PMID:21080962

2010-01-01

283

Carbon nanotube electron field emitters for x-ray imaging of human breast cancer  

NASA Astrophysics Data System (ADS)

For imaging human breast cancer, digital breast tomosynthesis (DBT) has been shown to improve image quality and breast cancer detection in comparison to two-dimensional (2D) mammography. Current DBT systems have limited spatial resolution and lengthy scan times. Stationary DBT (s-DBT), utilizing an array of carbon nanotube (CNT) field emission x-ray sources, provides increased spatial resolution and potentially faster imaging than current DBT systems. This study presents the results of detailed evaluations of CNT cathodes for x-ray breast imaging tasks. The following were investigated: high current, long-term stability of CNT cathodes for DBT; feasibility of using CNT cathodes to perform a 2D radiograph function; and cathode performance through several years of imaging. Results show that a breast tomosynthesis system using CNT cathodes could run far beyond the experimentally tested lifetime of one to two years. CNT cathodes were found capable of producing higher currents than typical DBT would require, indicating that the s-DBT imaging time can be further reduced. The feasibility of using a single cathode of the s-DBT tube to perform 2D mammography in 4 s was demonstrated. Over the lifetime of the prototype s-DBT system, it was found that both cathode performance and transmission rate were stable and consistent.

Gidcumb, Emily; Gao, Bo; Shan, Jing; Inscoe, Christy; Lu, Jianping; Zhou, Otto

2014-06-01

284

Carbon nanotube electron field emitters for x-ray imaging of human breast cancer.  

PubMed

For imaging human breast cancer, digital breast tomosynthesis (DBT) has been shown to improve image quality and breast cancer detection in comparison to two-dimensional (2D) mammography. Current DBT systems have limited spatial resolution and lengthy scan times. Stationary DBT (s-DBT), utilizing an array of carbon nanotube (CNT) field emission x-ray sources, provides increased spatial resolution and potentially faster imaging than current DBT systems. This study presents the results of detailed evaluations of CNT cathodes for x-ray breast imaging tasks. The following were investigated: high current, long-term stability of CNT cathodes for DBT; feasibility of using CNT cathodes to perform a 2D radiograph function; and cathode performance through several years of imaging. Results show that a breast tomosynthesis system using CNT cathodes could run far beyond the experimentally tested lifetime of one to two years. CNT cathodes were found capable of producing higher currents than typical DBT would require, indicating that the s-DBT imaging time can be further reduced. The feasibility of using a single cathode of the s-DBT tube to perform 2D mammography in 4 s was demonstrated. Over the lifetime of the prototype s-DBT system, it was found that both cathode performance and transmission rate were stable and consistent. PMID:24869902

Gidcumb, Emily; Gao, Bo; Shan, Jing; Inscoe, Christy; Lu, Jianping; Zhou, Otto

2014-06-20

285

In vitro estrogen-binding by human breast carcinomas.  

PubMed Central

Patients whose breast carcinomas possess only low concentrations of a receptor molecule that binds estrogens with high affinity are unlikely to respond to hormonal manipulative therapy when the disease recurs. The estrogen-binding capacity of 106 breast carcinomas was measured by an in vitro method and was expressed per milligram wet weight and in some cases related to the concentration of deoxyribonucleic acid (DNA) of the tumours. The ability of tumors to bind 3H-estradiol ranged from 0 to 1.3 fm/mg in pre- and perenopausal women, and from 0 to 16.8 fm/mg in postmenopausal women. Menopausal status or serum concentrations of endogenous estrogen, or both, should therefore be considered when tumours are classified into low and high estrogen-binding capacity. It is not necessary to carry out Scatchard analysis for every tumour, and expressing estradiol binding on the basis of DNA concentration may be preferable to expressing in on a wet-weight basis. PMID:1032352

Mobbs, B. G.; Johnson, I. E.

1976-01-01

286

Effect of human, bovine and ovine prolactin on DNA synthesis by organ cultures of benign human breast tumours.  

PubMed

Ten benign breast tumours from 9 female patients (8 with fibrocystic disease and 1 with fibroadenoma) and 1 male patient (with gynaecomastia) were processed into slices and individually cultured for 2 days in serum-free Medium 199. [3H]-TdR was added to the culture medium to assess DNA synthesis. The addition of human prolactin to the culture medium (500 ng/ml) significantly (0.05 greater than P greater than 0.01) increased DNA synthesis; all 9 biopsy specimens from the 9 female patients responded positively to this hormone. Ovine prolactin (500 ng/ml) and bovine prolactin (500 ng/ml) increased the mean incorporation of [3H]-TdR into extracted DNA and increased the mean number of [3H]-TdR-labelled cells, but this increase did not reach the 5% level of probability. The sole case of male breast dysplasia analysed in this study did not respond to either human, ovine or bovine prolactin. These results provide evidence that human prolactin and, to a lesser degree, ovine and bovine prolactin are direct mitogenic stimulants to the epithelium in human (female) benign breast tumours. PMID:575047

Welsch, C W; Dombroske, S E; McManus, M J; Calaf, G

1979-12-01

287

Effect of human, bovine and ovine prolactin on DNA synthesis by organ cultures of benign human breast tumours.  

PubMed Central

Ten benign breast tumours from 9 female patients (8 with fibrocystic disease and 1 with fibroadenoma) and 1 male patient (with gynaecomastia) were processed into slices and individually cultured for 2 days in serum-free Medium 199. [3H]-TdR was added to the culture medium to assess DNA synthesis. The addition of human prolactin to the culture medium (500 ng/ml) significantly (0.05 greater than P greater than 0.01) increased DNA synthesis; all 9 biopsy specimens from the 9 female patients responded positively to this hormone. Ovine prolactin (500 ng/ml) and bovine prolactin (500 ng/ml) increased the mean incorporation of [3H]-TdR into extracted DNA and increased the mean number of [3H]-TdR-labelled cells, but this increase did not reach the 5% level of probability. The sole case of male breast dysplasia analysed in this study did not respond to either human, ovine or bovine prolactin. These results provide evidence that human prolactin and, to a lesser degree, ovine and bovine prolactin are direct mitogenic stimulants to the epithelium in human (female) benign breast tumours. PMID:575047

Welsch, C. W.; Dombroske, S. E.; McManus, M. J.; Calaf, G.

1979-01-01

288

Protein kinase C is differentially regulated by thrombin, insulin, and epidermal growth factor in human mammary tumor cells  

SciTech Connect

The exposure of serum-deprived mammary tumor cells MCF-7 and T-47D to insulin, thrombin, and epidermal growth factor (EGF) resulted in dramatic modifications in the activity and in the translocation capacity of protein kinase C from cytosol to membrane fractions. Insulin induces a 600% activation of the enzyme after 5 h of exposure to the hormone in MCF-7 cells; thrombin either activates (200% in MCF-7) or down-regulates (in T-47D), and EGF exerts only a moderate effect. Thus, the growth factors studied modulate differentially the protein kinase C activity in human mammary tumor cells. The physiological significance of the results obtained are discussed in terms of the growth response elicited by insulin, thrombin, and EGF.

Gomez, M.L.; Tellez-Inon, M.T. (Instituto de Ingenieria Genetica y Biologia Molecular, Buenos Aires (Argentina)); Medrano, E.E.; Cafferatta, E.G.A. (Instituto de Investigaciones Bioquimicas Fundacion Campomar, Buenos Aires (Argentina))

1988-03-01

289

Prolactin-Induced Protein (PIP) Regulates Proliferation of Luminal A Type Breast Cancer Cells in an Estrogen-Independent Manner  

PubMed Central

Prolactin-induced Protein (PIP), an aspartyl protease unessential for normal mammalian cell function, is required for the proliferation and invasion of some breast cancer (BCa) cell types. Because PIP expression is particularly high in the Luminal A BCa subtype, we investigated the roles of PIP in the related T47D BCa cell line. Nucleic acid and antibody arrays were employed to screen effects of PIP silencing on global gene expression and activation of receptor tyrosine kinases (RTKs), respectively. Expression of PIP-stimulated genes, as defined in the T47D cell culture model, was well correlated with the expression of PIP itself across a cohort of 557 mRNA profiles of diverse BCa tumors, and bioinformatics analysis revealed cJUN and cMYC as major nodes in the PIP-dependent gene network. Among 71 RTKs tested, PIP silencing resulted in decreased phosphorylation of focal adhesion kinase (FAK), ephrin B3 (EphB3), FYN, and hemopoietic cell kinase (HCK). Ablation of PIP also abrogated serum-induced activation of the downstream serine/threonine kinases AKT, ERK1/2, and JNK1. Consistent with these results, PIP-depleted cells exhibited defects in adhesion to fibronectin, cytoskeletal stress fiber assembly and protein secretion. In addition, PIP silencing abrogated the mitogenic response of T47D BCa cells to estradiol (E2). The dependence of BCa cell proliferation was unrelated, however, to estrogen signaling because: 1) PIP silencing did not affect the transcriptional response of estrogen target genes to hormone treatment, and 2) PIP was required for the proliferation of tamoxifen-resistant BCa cells. Pharmacological inhibition of PIP may therefore serve the bases for both augmentation of existing therapies for hormone-dependent tumors and the development of novel therapeutic approaches for hormone-resistant BCa. PMID:23755096

Baniwal, Sanjeev K.; Chimge, Nyam-Osor; Jordan, V. Craig; Tripathy, Debu; Frenkel, Baruch

2013-01-01

290

Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer  

PubMed Central

Components of the plasminogen activation system (PAS) which are overexpressed in aggressive breast cancer subtypes offer appealing targets for development of new diagnostics and therapeutics. By comparing gene expression data in patient populations and cultured cell lines, we identified elevated levels of the urokinase plasminogen activation receptor (uPAR, PLAUR) in highly aggressive breast cancer subtypes and cell lines. Recombinant human anti-uPAR antagonistic antibodies exhibited potent binding in vitro to the surface of cancer cells expressing uPAR. In vivo these antibodies detected uPAR expression in triple negative breast cancer (TNBC) tumor xenografts using near infrared (NIR) imaging and 111In single-photon emission computed tomography (SPECT). Antibody-based uPAR imaging probes accurately detected small disseminated lesions in a tumor metastasis model, complementing the current clinical imaging standard 18F-fluorodeoxyglucose (FDG) at detecting non-glucose-avid metastatic lesions. A monotherapy study using the antagonistic antibodies resulted in a significant decrease in tumor growth in a TNBC xenograft model. Additionally, a radioimmunotherapy (RIT) study, using the anti-uPAR antibodies conjugated to the therapeutic radioisotope 177Lu, found that they were effective at reducing tumor burden in vivo. Taken together, our results offer a preclinical proof of concept for uPAR targeting as a strategy for breast cancer diagnosis and therapy using this novel human antibody technology. PMID:23400595

LeBeau, Aaron M.; Duriseti, Sai; Murphy, Stephanie T.; Pepin, Francois; Hann, Byron; Gray, Joe W.; VanBrocklin, Henry F.; Craik, Charles S.

2013-01-01

291

Sensitive detection of human breast cancer cells based on aptamer-cell-aptamer sandwich architecture.  

PubMed

Breast cancer is one of the most critical threats to the health of women, and the development of new methods for early diagnosis is urgently required, so this paper reports a method to detect Michigan cancer foundation-7 (MCF-7) human breast cancer cells with considerable sensitivity and selectivity by using electrochemical technique. In this method, a mucin 1 (MUC1)-binding aptamer is adopted to recognize MCF-7 human breast cancer cells, while enzyme labeling is employed to produce amplified catalytic signals. The molecular recognition and the signal amplification are elaborately integrated by fabricating an aptamer-cell-aptamer sandwich architecture on an electrode surface, thus a biosensor for the detection of MCF-7 is fabricated based on the architecture. The detection range can be from 100 to 1×10(7) cells, and the detection limit can be as low as 100 cells. The method is also cost-effective and conveniently operated, implying potential help for the development of early diagnosis of breast cancer. PMID:23374215

Zhu, Xiaoli; Yang, Jinghua; Liu, Min; Wu, Yao; Shen, Zhongming; Li, Genxi

2013-02-18

292

Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer  

PubMed Central

Lipocalin 2 (Lcn2), a member of the lipocalin family, is up-regulated in a variety of epithelial cancers. We have previously reported that Lcn2 induces the epithelial to mesenchymal transition in breast cancer through the estrogen receptor ?/Slug axis and that it is a potential noninvasive biomarker of this disease. Here, we report the novel finding that Lcn2 regulates breast cancer angiogenesis. Vascular endothelial growth factor (VEGF), a key angiogenic activator, was significantly increased with Lcn2 expression in MCF-7 human breast cancer cells as well as in an angiogenic line derived from MDA-MB-436 cells. Treatment with a VEGF-neutralizing antibody demonstrates that VEGF is essential for the angiogenic activity of Lcn2. We further demonstrate that Lcn2-induced VEGF is mediated through hypoxia-inducible factor 1? (HIF-1?) and that Lcn2 regulates HIF-1? through extracellular signal-regulated kinase (Erk). The regulation of HIF-1? and VEGF by Lcn2 was also demonstrated in the aggressive MDA-MB-231 cell line. Using the mouse corneal pocket assay, we found that Lcn2 significantly enhanced the angiogenesis induced by VEGF. Taken together, these results are the first to demonstrate that Lcn2 promotes angiogenesis in vitro and in vivo and suggest a novel mechanism through which Lcn2 may promote tumor progression.—Yang, J., McNeish, B., Butterfield, C., Moses, M. A. Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer. PMID:22982376

Yang, Jiang; McNeish, Brendan; Butterfield, Catherine; Moses, Marsha A.

2013-01-01

293

Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure.  

PubMed

It has been suggested that xenoestrogens, a group of agents termed endocrine disruptors, may contribute to the development of hormone-dependent cancers, such as breast and endometrial cancers. We previously demonstrated that the xenoestrogen, bisphenol A (BPA), was able to induce the transformation in vitro of human breast epithelial cells. The normal-like human breast epithelial cell line, MCF-10F, formed tubules in collagen (3-D cultures), although after treatment with BPA (10-5 M and 10-6 M BPA) the cells produced less tubules (73% and 80%, respectively) and some spherical masses (27% and 20%, respectively). In the present study, expression and DNA methylation analyses were performed in these cells after exposure to BPA. These cells showed an increased expression of BRCA1, BRCA2, BARD1, CtIP, RAD51 and BRCC3, all of which are genes involved in DNA repair, as well as the downregulation of PDCD5 and BCL2L11 (BIM), both of which are involved in apoptosis. Furthermore, DNA methylation analysis showed that the BPA exposure induced the hypermethylation of BCL2L11, PARD6G, FOXP1 and SFRS11, as well as the hypomethylation of NUP98 and CtIP (RBBP8). Our results indicate that normal human breast epithelial cells exposed to BPA have increased expressions of genes involved in DNA repair in order to overcome the DNA damage induced by this chemical. These results suggest that the breast tissue of women with BRCA1 or BRCA2 mutations could be more susceptible to the effects of BPA. PMID:22576693

Fernandez, Sandra V; Huang, Yong; Snider, Kara E; Zhou, Yan; Pogash, Thomas J; Russo, Jose

2012-07-01

294

Modulation of doxorubicin cytotoxicity by resveratrol in a human breast cancer cell line  

PubMed Central

Background Breast cancer is the most common cancer in the Arab world and it ranked first among Saudi females. Doxorubicin (DOX), an anthracycline antibiotic is one of the most effective anticancer agents used to treat breast cancer. chronic cardiotoxicity is a major limiting factor of the use of doxorubicin. Therefore, our study was designed to assess the role of a natural product resveratrol (RSVL) on sensitization of human breast cancer cells (MCF-7) to the action of DOX in an attempt to minimize doxorubicin effective dose and thereby its side effects. Methods Human breast cancer cell line MCF-7, was used in this study. Cytotoxic activity of DOX was determined using (sulforhodamine) SRB method. Apoptotic cells were quantified after treatment by annexin V-FITC- propidium iodide (PI) double staining using flow-cytometer. Cell cycle disturbance and doxorubicin uptake were determined after RSVL or DOX treatment. Results Treatment of MCF-7 cells with 15 ?g/ml RSVL either simultaneously or 24 h before DOX increased the cytotoxicity of DOX, with IC50 were 0.056 and 0.035 ?g/ml, respectively compared to DOX alone IC50 (0.417 ?g/ml). Moreover, flow cytometric analysis of the MCF-7 cells treated simultaneously with DOX (0.5 ?g/ml) and RSVL showed enhanced arrest of the cells in G0 (80%). On the other hand, when RSVL is given 24 h before DOX although there was more increased in the cytotoxic effect of DOX against the growth of the cells, however, there was decreased in percentage arrest of cells in G0, less inhibition of DOX-induced apoptosis and reduced DOX cellular uptake into the cells. Conclusion RSVL treatment increased the cytotoxic activity of DOX against the growth of human breast cancer cells when given either simultaneously or 24 h before DOX. PMID:23153194

2012-01-01

295

Clotrimazole Preferentially Inhibits Human Breast Cancer Cell Proliferation, Viability and Glycolysis  

PubMed Central

Background Clotrimazole is an azole derivative with promising anti-cancer effects. This drug interferes with the activity of glycolytic enzymes altering their cellular distribution and inhibiting their activities. The aim of the present study was to analyze the effects of clotrimazole on the growth pattern of breast cancer cells correlating with their metabolic profiles. Methodology/Principal Findings Three cell lines derived from human breast tissue (MCF10A, MCF-7 and MDA-MB-231) that present increasingly aggressive profiles were used. Clotrimazole induces a dose-dependent decrease in glucose uptake in all three cell lines, with Ki values of 114.3±11.7, 77.1±7.8 and 37.8±4.2 µM for MCF10A, MCF-7 and MDA-MB-231, respectively. Furthermore, the drug also decreases intracellular ATP content and inhibits the major glycolytic enzymes, hexokinase, phosphofructokinase-1 and pyruvate kinase, especially in the highly metastatic cell line, MDA-MB-231. In this last cell lineage, clotrimazole attenuates the robust migratory response, an effect that is progressively attenuated in MCF-7 and MCF10A, respectively. Moreover, clotrimazole reduces the viability of breast cancer cells, which is more pronounced on MDA-MB-231. Conclusions/Significance Clotrimazole presents deleterious effects on two human breast cancer cell lines metabolism, growth and migration, where the most aggressive cell line is more affected by the drug. Moreover, clotrimazole presents little or no effect on a non-tumor human breast cell line. These results suggest, at least for these three cell lines studied, that the more aggressive the cell is the more effective clotrimazole is. PMID:22347377

Furtado, Cristiane M.; Marcondes, Mariah C.; Sola-Penna, Mauro; de Souza, Maisa L. S.; Zancan, Patricia

2012-01-01

296

Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans.  

PubMed

Skeletal metastases of breast cancer and subsequent osteolysis connote a dramatic change in the prognosis for the patient and significantly increase the morbidity associated with disease. The cytokine interleukin 8 (IL-8/CXCL8) is able to directly stimulate osteoclastogenesis and bone resorption in mouse models of breast cancer bone metastasis. In this study, we determined whether circulating levels of IL-8 were associated with increased bone resorption and breast cancer bone metastasis in patients and investigated IL-8 action in vitro and in vivo in mice. Using breast cancer patient plasma (36 patients), we identified significantly elevated IL-8 levels in bone metastasis patients compared with patients lacking bone metastasis (p<0.05), as well as a correlation between plasma IL-8 and increased bone resorption (p<0.05), as measured by NTx levels. In a total of 22 ER+ and 15 ER- primary invasive ductal carcinomas, all cases examined stained positive for IL-8 expression. In vitro, human MDA-MB-231 and MDA-MET breast cancer cell lines secrete two distinct IL-8 isoforms, both of which were found to stimulate osteoclastogenesis. However, the more osteolytic MDA-MET-derived full length IL-8(1-77) had significantly higher potency than the non-osteolytic MDA-MB-231-derived IL-8(6-77), via the CXCR1 receptor. MDA-MET breast cancer cells were injected into the tibia of nude mice and 7days later treated daily with a neutralizing IL-8 monoclonal antibody. All tumor-injected mice receiving no antibody developed large osteolytic bone tumors, whereas 83% of the IL-8 antibody-treated mice had no evidence of tumor at the end of 28days and had significantly increased survival. The pro-osteoclastogenic activity of IL-8 in vivo was confirmed when transgenic mice expressing human IL-8 were examined and found to have a profound osteopenic phenotype, with elevated bone resorption and inherently low bone mass. Collectively, these data suggest that IL-8 plays an important role in breast cancer osteolysis and that anti-IL-8 therapy may be useful in the treatment of the skeletal related events associated with breast cancer. PMID:24486955

Kamalakar, Archana; Bendre, Manali S; Washam, Charity L; Fowler, Tristan W; Carver, Adam; Dilley, Joshua D; Bracey, John W; Akel, Nisreen S; Margulies, Aaron G; Skinner, Robert A; Swain, Frances L; Hogue, William R; Montgomery, Corey O; Lahiji, Parshawn; Maher, Jacqueline J; Leitzel, Kim E; Ali, Suhail M; Lipton, Alan; Nicholas, Richard W; Gaddy, Dana; Suva, Larry J

2014-04-01

297

Mechanisms of hormonal regulation of CAD gene expression and inhibition by Aryl hydrocarbon receptor agonist in human breast cancer cells  

E-print Network

The CAD gene is trifunctional and expresses carbamoylphosphate synthetase/aspartate carbamyltransferase/dihydroorotase, which are required for pyrimidine biosynthesis. CAD gene activities are induced in MCF-7 human breast cancer cells, and treatment...

Khan, Shaheen Munawar Ali

2007-04-25

298

Regulation of BRCA2 Gene Expression by the SLUG Repressor Protein in Human Breast Cells*  

PubMed Central

The expression of the breast cancer susceptibility protein BRCA2 is highly regulated in human breast, ovary, and pancreatic cells. BRCA2 is not expressed in the non-dividing cells, and expression is cell cycle stage-dependent and is elevated in the sporadic cancer cells. Mutational analysis of the upstream sequence of the human BRCA2 gene revealed an E2-box-containing silencer at the ?701 to ?921 position. The E2-box is essential for the cell-cycle stage-dependent activity of the silencer. We affinity-purified a 29-kDa silencer-binding protein (SBP) from the nuclear extracts of human breast cells BT-549 and MDA-MB-231. We explored whether the E2-box-binding repressor protein SLUG, which is of similar molecular size, is involved in the silencing process. Supershift assay with the purified SBP and anti-SLUG antibody revealed the identity of the SBP as SLUG. We found that silencer is inactive in the human breast cancer cells such as MDA-MB-468 and MCF-7 that do not express SLUG, further suggesting the involvement of SLUG in the BRCA2 gene silencing. Inducible expression of human SLUG in the dividing MDA-MB-468 cells reduced BRCA2 RNA levels with the activation of the silencer. Furthermore, small interfering RNA-mediated knockdown of SLUG mRNA in the BT-549 cells caused inhibition of the silencer function. Chromatin immunoprecipitation assays suggested that SLUG mediates its action by recruiting C-terminal-binding protein-1 (CtBP-1) and histone deacetylase-1 (HDAC-1) at the silencer E2-box. The general HDAC inhibitor, trichostatin A, inhibited the SLUG-mediated regulation of the silencer function. It thus appears that SLUG is a negative regulator for BRCA2 gene expression. PMID:15734731

Tripathi, Manish K.; Misra, Smita; Khedkar, Sheetal V.; Hamilton, Nalo; Irvin-Wilson, Charletha; Sharan, Chakradhari; Sealy, Linda; Chaudhuri, Gautam

2011-01-01

299

Suppression of growth of highly-metastatic human breast cancer cells by norcantharidin and its mechanisms of action  

Microsoft Academic Search

The effects of norcantharidin (NCTD) on the growth of highly-metastatic human breast cancer cells were investigated by in\\u000a vitro and ex vivo assays. Our results indicated that norcantharidin inhibited the in vitro growth of human breast cancer MDA-MB-231\\u000a cell line in dose- and time-dependent manners after the cancer cells were treated with norcantharidin at the concentrations\\u000a of 6, 30 and

Yan Huang; Qian Liu; Kun Liu; Kazumi Yagasaki; Guoying Zhang

2009-01-01

300

Induction of E-cadherin endocytosis by loss of protein phosphatase 2A expression in human breast cancers  

Microsoft Academic Search

The cell–cell adhesion molecule E-cadherin is stabilized by linking intracellularly with the actin cytoskeleton through PP2A-mediated recruitment of IQGAP1 to Rac1-bound E-cadherin–catenins complex in nonmalignant HME cells. However, little is known about the dysfunction of E-cadherin by loss or reduced expression of PP2A in human breast cancer cells. We report here that both human breast cancer MDA-MB-231 and MCF-7 cells

Katsuo Suzuki; Kazuhide Takahashi

2006-01-01

301

Induction of human breast cell carcinogenesis by triclocarban and intervention by curcumin  

SciTech Connect

Highlights: •Triclocarban exposure induces breast epithelial cell carcinogenesis. •Triclocarban induces the Erk–Nox pathway, ROS elevation, and DNA damage. •Physiological doses of triclocarban induce cellular carcinogenesis. •Non-cytotoxic curcumin blocks triclocarban-induced carcinogenesis and pathways. -- Abstract: More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens and co-carcinogens. To identify co-carcinogens with abilities to induce cellular pre-malignancy, we studied the activity of triclocarban (TCC), an antimicrobial agent commonly used in household and personal care products. Here, we demonstrated, for the first time, that chronic exposure to TCC at physiologically-achievable nanomolar concentrations resulted in progressive carcinogenesis of human breast cells from non-cancerous to pre-malignant. Pre-malignant carcinogenesis was measured by increasingly-acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth and increased cell proliferation, without acquisition of cellular tumorigenicity. Long-term TCC exposure also induced constitutive activation of the Erk–Nox pathway and increases of reactive oxygen species (ROS) in cells. A single TCC exposure induced transient induction of the Erk–Nox pathway, ROS elevation, increased cell proliferation, and DNA damage in not only non-cancerous breast cells but also breast cancer cells. Using these constitutively- and transiently-induced changes as endpoints, we revealed that non-cytotoxic curcumin was effective in intervention of TCC-induced cellular pre-malignancy. Our results lead us to suggest that the co-carcinogenic potential of TCC should be seriously considered in epidemiological studies to reveal the significance of TCC in the development of sporadic breast cancer. Using TCC-induced transient and constitutive endpoints as targets will likely help identify non-cytotoxic preventive agents, such as curcumin, effective in suppressing TCC-induced cellular pre-malignancy.

Sood, Shilpa; Choudhary, Shambhunath; Wang, Hwa-Chain Robert, E-mail: hcrwang@utk.edu

2013-09-06

302

Ginsenoside Rc and Re stimulate c-fos expression in MCF-7 human breast carcinoma cells.  

PubMed

We have found that ginsenoside Rc and Re induce c-fos in MCF-7 human breast carcinoma cells at both the mRNA and protein levels. However, neither ginsenoside activated the expression of reporter gene under the control of AP-1/TPA response elements. We have also examined the possibility that ginsenoside Rc and Re act by binding to intracellular steroid hormone receptors that act as transcriptional factors in the nucleus in inducing c-fos mRNA in MCF7 human breast carcinoma cells. However, ginsenoside Rc and Re did not bind to glucocorticoid, androgen, estrogen, or retinoic acid receptors as examined by the transcription activation of the luciferase reporter genes in CV-1 cells that were transiently transfected with the corresponding steroid hormone receptors and hormone responsive luciferase reporter plasmids. These data demonstrate that ginsenoside Rc and Re act via other transcription factors and not via estrogen receptor in c-Fos expression. PMID:12568359

Lee, Young Joo; Jin, Young Ran; Lim, Won Chung; Ji, Sang Mi; Cho, Jung Yoon; Ban, Jae Jun; Lee, Seung Ki

2003-01-01

303

Estradiol inhibits glucocorticoid receptor expression and induces glucocorticoid resistance in MCF7 human breast cancer cells  

Microsoft Academic Search

Our study has shown that treatment of MCF-7 human breast cancer cells with 17-? estradiol (E2) produced significant decreases in glucocorticoid receptor (GR) concentrations and GR mRNA levels. E2 pre-treatment of MCF-7 cells stably transfected with the GR responsive pMTV-CAT reporter (MCF-7–MTV cells), caused significant attenuation of dexamethasone (DEX)-induced chloramphenicol acetyl transferase (CAT). In MCF-7 cells transiently transfected with [(GRE)3-Luc

Aruna V Krishnan; Srilatha Swami; David Feldman

2001-01-01

304

Specific pattern of persistent organochlorine residues in human breast milk from South India  

Microsoft Academic Search

Human breast milk samples collected from four locations in Tamil Nadu state, South India, were analyzed for understanding the levels of persistent organochlorines such as 1,2,3,4,5,6-hexachlorocyclohexane (HCH (BHC)) isomers, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) compounds, and polychlorinated biphenyls (PCBs). On the basis of the overall concentrations of these compounds, ΣHCH (sum of α, β, γ, and δ isomers) levels were higher than the

Shinsuke Tanabe; Futoshi Gondaira; A. Ramesh; Ryo Tatsukawa; A. Subramanian; D. Mohan; P. Kumaran; V. K. Venugopalan

1990-01-01

305

CEA-like material in cytosols from human breast carcinomas. Correlation with biochemical and pathologic parameters.  

PubMed

CEA-like material was found in 51 of 62 primary human breast carcinomas and in only 2 of 12 fibroadenomas. Levels of carcinoma CEA-like material correlated weakly with cytoplasmic estradiol receptor levels, total cytosol estrogens, and cytosol progesterone. Levels of CEA-like material showed no significant correlation with carcinoma stage, grade, cellularity, size or histologic type. Levels, however, correlated inversely with lymphocyte infiltration. PMID:6295590

Duffy, M J; O'Connell, M; O'Sullivan, F; McKenna, B; Allen, M A; McDonnell, L

1983-01-01

306

Persistent Organochlorine Compounds in Human Breast Milk from Mothers Living in Penang and Kedah, Malaysia  

Microsoft Academic Search

This study determined the concentrations of polychlorinated dibenzo-p-dioxins\\/dibenzofurans (PCDD\\/Fs), polychlorinated biphenyls (PCBs), organochlorine (OC) pesticides, and tris(4-chlorophenyl) methane (TCPMe) in human breast milk samples collected in 2003 from primipara mothers living in Penang, Malaysia. OCs were detected in all the samples analyzed with DDTs, hexachlorocyclohexane isomers (HCHs), and PCBs as the major contaminants followed by chlordane compounds (CHLs), hexachlorobenzene (HCB),

Agus Sudaryanto; Tatsuya Kunisue; Shinsuke Tanabe; Mami Niida; Hatijah Hashim

2005-01-01

307

Reduced Expression of GNA11 and Silencing of MCT1 in Human Breast Cancers  

Microsoft Academic Search

Alteration in the methylation status of a gene is often associated with its altered expression. Based on a genome scanning technique for differences in CpG methylations, methylation-sensitive representational difference analysis, DNA fragments hypermethylated in a human breast cancer were isolated. A DNA fragment was isolated from intron 1 of guanine-nucleotide-binding protein ?-11 (GNA11). mRNA expression of GNA11 was shown to

Kiyoshi Asada; Kazuaki Miyamoto; Takashi Fukutomi; Hitoshi Tsuda; Yukiko Yagi; Kuniko Wakazono; Shoko Oishi; Hiroshi Fukui; Takashi Sugimura; Toshikazu Ushijima

2003-01-01

308

An aberrant spliced transcript of focal adhesion kinase is exclusively expressed in human breast cancer  

PubMed Central

Purpose To clarify the roles of a new aberrantly spliced transcript of FAK that lacks exon 26 (denoted -26-exon FAK) in human breast cancers. Methods Transcripts of FAK expressed in 102 human breast tumor tissues and 52 corresponding normal tissues were analyzed by RT-PCR and DNA sequencing, as well as agarose gel electrophoresis. The cDNA of -26-exon FAK was cloned and expressed in MCF-10A cells, and then the kinase activity, cellular localization and migration capability of FAK were examined by western blotting, immunofluorescent staining and migration assays, respectively. The expression levels of FAK were analyzed by western blotting in MCF-7 cells treated with TNF-? or in MCF-10A cells upon serum deprivation. The MCF-10A cells transfected with a plasmid expressing -26-exon FAK were cultured in serum-free medium and cell apoptosis was analyzed by flow cytometry. Results The -26-exon FAK transcript was exclusively present in human breast tumor tissues and the encoded protein possessed the same kinase activity, cellular localization and cell migration-promoting ability as wild-type FAK. In MCF-7 cells treated with TNF-?, and in MCF-10A cells upon serum deprivation, the -26-exon FAK was resistant to proteolysis while wild-type FAK was largely cleaved. In addition, the -26-exon FAK, but not wild-type FAK, inhibited cell apoptosis. Conclusions The -26-exon FAK transcript, which is exclusively expressed in human breast tumor tissues, encodes a protein that possesses the same kinase activity and biological function as the wild-type FAK, but because it is resistant to the caspase-mediated cleavage that induces the proteolysis of the wild-type form, it ultimately prevents apoptosis. PMID:24885534

2014-01-01

309

Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines  

Microsoft Academic Search

Introduction  Thoracic malignancies and human breast cancer (HBC) continue to be aggressive solid tumors that are poor responders to the\\u000a existing conventional standard chemotherapeutic approaches. Malignant pleural mesothelioma (MPM) is an asbestos-related tumor\\u000a of the thoracic pleura that lacks effective treatment options. Altered ubiquitin proteasome pathway is frequently encountered\\u000a in many malignancies including HBC and MPM and thus serves as an

Ying Wang; Arun K. Rishi; Vineshkumar T. Puliyappadamba; Sunita Sharma; Huanjie Yang; Adi Tarca; Q. Ping Dou; Fulvio Lonardo; John C. Ruckdeschel; Harvey I. Pass; Anil Wali

2010-01-01

310

Ginsenoside Rc and Re stimulate c-Fos expression in MCF7 human breast carcinoma cells  

Microsoft Academic Search

We have found that ginsenoside Rc and Re induce c-fos in MCF-7 human breast carcinoma cells at both the mRNA and protein levels.\\u000a However, neither ginsenoside activated the expression of reporter gene under the control of AP-1\\/TPA response elements. We\\u000a have also examined the possibility that ginsenoside Rc and Re act by binding to intracellular steroid hormone receptors that\\u000a act

Young Joo Lee; Young Ran Jin; Won Chung Lim; Sang Mi Ji; Jung Yoon Cho; Jae Jun Ban; Seung Ki Lee

2003-01-01

311

Estradiol 17 beta-hydroxysteroid dehydrogenase activity in human breast fibroadenomas.  

PubMed

In the human endometrium, the presence of the progesterone-dependent enzyme 17 beta-hydroxysteroid dehydrogenase (E2DH) permits the conversion of an active estrogen, estradiol, into a less active one, estrone. This E2DH activity contributes to the antiestrogenic properties of progesterone. In the present study, E2DH activity was assayed in 54 surgically removed fibroadenomas. This benign breast disease was chosen since it offers rather homogeneous epithelial concentrations and still remains close to normal breast tissue from a pathological and hormonal point of view. E2DH activity was highest in fibroadenomas with high epithelial cell density. In addition, in these high epithelial cell density fibroadenomas (n = 18), E2DH activity increased markedly throughout the luteal phase of the menstrual cycle. Thus, it was 3- to 4-fold higher in fibroadenomas removed at the end of the luteal phase (1520 +/- 166 fmol/mg protein.h) than in those obtained during the follicular phase (375 +/- 95 fmol/mg protein.h). In addition, a striking increase in E2DH activity was observed in fibroadenomas from 5 patients treated with oral progestins (4080 +/- 650 fmol/mg protein.h) and 3 patients receiving progesterone topically applied upon the breast (3830 +/- 475 fmol/mg protein.h). E2DH activity, therefore, appears to be an important mechanism involved in the control by progesterone of estradiol action in breast tissue, as it is in the endometrium. It is also a good index of cellular differentiation and progesterone action at the molecular level. It is hypothesized that E2DH activity might be a specific marker of progesterone receptor itself and could be proposed in the evaluation of the hormone dependence of human breast tissue. PMID:6954155

Fournier, S; Kuttenn, F; de Cicco, F; Baudot, N; Malet, C; Mauvais-Jarvis, P

1982-09-01

312

EZH2 knockdown suppresses the growth and invasion of human inflammatory breast cancer cells  

PubMed Central

Introduction Inflammatory breast cancer (IBC) is the most metastatic variant of breast cancer with the poorest survival in all types of breast cancer patients and presently therapeutic targets for IBC are very limited. Enhancer of zeste homolog 2 (EZH2) is frequently expressed in human IBC and its expression positively correlates with worse clinical outcome. However, the molecular basis for EZH2 promoting IBC has not been explored. Here, we investigated the functional role of EZH2 in IBC cells by examining the effects of its knockdown on the formation of tumor spheroids and invasion of these cells in vitro and in vivo in an orthotopic xenograft model. Methods SUM149 and a new IBC cell line-FC-IBC-02 derived from pleural effusion fluid of an IBC patient were used in this study. Specific knockdown of EZH2 was performed using short hairpin RNA (shRNA) specific to the human EZH2 gene. Cell growth and the formation of tumor spheroids were examined in vitro. The effects of EZH2 knockdown on IBC cell migration and invasion were examined by a Boyden chamber assay. For the in vivo tumor growth studies, IBC cells were orthotopically transplanted into the mammary fat pads of immunodeficient mice. Results The results showed that EZH2 is expressed at higher levels in human IBC cell lines compared with normal human mammary epithelial cells, and the knockdown of EZH2 expression significantly suppressed cell growth and tumor spheroid formation of human IBC cells in vitro. In addition, EZH2 knockdown inhibited the migration and invasion of IBC cells. Significantly, EZH2 knockdown suppressed the angiogenesis and tumor growth of IBC cells in vivo. Conclusions Our results provide direct evidence that EZH2 is critical for the formation of tumor spheroids and invasion of human IBC cells and could be a potential target for developing novel therapeutic strategies for human IBC. PMID:24294976

2013-01-01

313

Expression of prolactin and prolactin receptor in human breast carcinoma. Evidence for an autocrine/paracrine loop.  

PubMed Central

The neuroendocrine hormone prolactin is a growth factor required for the proliferation and terminal differentiation of the human breast. These effects are mediated by the prolactin receptor, a member of the growth factor receptor family. Three prolactin receptor isoforms (long, intermediate, and short) have been identified in the rat, which differ in the length of their intracytoplasmic domains. In humans, however, only the long prolactin receptor isoform had been identified previously. The expression of the human intermediate prolactin receptor is demonstrated and preliminary evidence for a human short isoform is presented. Heterogeneous expression of prolactin receptor, at the immunoblot and immunohistochemical levels was observed in breast carcinoma specimens. A statistically significant correlation between prolactin receptor and estrogen receptor expression was noted. An autocrine/paracrine role for prolactin within breast tissues was further examined by performing reverse transcription polymerase chain reaction on RNA isolated from cell lines and clinical specimens with prolactin-specific primers. A 585-bp product was observed and found to be identical to human prolactin. The synthesis of prolactin by breast epithelium was confirmed by in situ hybridization analysis of breast tissues and the detection of bio- and immunoreactive prolactin in breast cancer lines. These analyses indicate that the principal site for prolactin expression within the normal or malignant breast residues within the epithelium. These data indicate that prolactin may participate in an autocrine/paracrine stimulatory loop within breast tissues and suggest a role for this growth factor in the pathogenesis of breast cancer. Images Figure 1 Figure 4 Figure 3 Figure 5 PMID:7534043

Clevenger, C. V.; Chang, W. P.; Ngo, W.; Pasha, T. L.; Montone, K. T.; Tomaszewski, J. E.

1995-01-01

314

Expression of fibroblast growth factor 1 is lower in breast cancer than in the normal human breast.  

PubMed Central

We have measured the amount of fibroblast growth factor 1 (FGF-1) mRNA and protein in primary breast cancers and non-malignant breast tissue and have found greatly reduced levels in breast cancer compared with non-malignant tissue. A total of 116 breast cancers and 37 biopsies taken from non-malignant breast were compared for FGF-1 mRNA expression using reverse transcriptase-polymerase chain reaction (RT-PCR) and significantly lower levels were found in the cancer tissues (P < 0.001). These findings were confirmed at the protein level where four out of five breast cancers contained no detectable FGF-1 and a fifth cancer had a low level of FGF-1 compared with three samples from reduction mammoplasties. Similar results were obtained from breast cell lines in which 80% of cancer cell lines had very low levels of FGF-1, whereas all non-malignant breast cell lines contained higher levels of FGF-1. Immunohistochemical analysis indicated that FGF-1 was present in the luminal epithelial cells of the non-malignant breast but was absent from cancer cells. The decreased levels of FGF-1 in breast cancer may indicate that stimulation of cancer cells is resulting in down-regulation of FGF-1 expression or may implicate FGF-1 as a differentiation factor rather than a growth factor at its physiological concentration in the breast. Images Figure 2 Figure 3 Figure 5 PMID:8519654

Bansal, G. S.; Yiangou, C.; Coope, R. C.; Gomm, J. J.; Luqmani, Y. A.; Coombes, R. C.; Johnston, C. L.

1995-01-01

315

Rapid sample preparation procedure for determination of retinol and ?-tocopherol in human breast milk.  

PubMed

The liposoluble vitamins (retinol and ?-tocopherol) concentration in human breast milk is of a cardinal knowledge especially for nutrition of prematurely born. It enables the feeding optimization of these important micronutrients for preterm infants. The novel rapid liquid-liquid extraction procedure for human breast milk investigation was developed and validated according to FDA guidelines. The recovery of retinol was 82-90% measured at three concentration levels 1.0, 2.5 and 5.0 ?mol/L, for ?-tocopherol 92-109% at concentration levels 2.5, 5.0 and 10.0 ?mol/L. The repeatability of extraction procedure expressed as relative standard deviation was 3.26% for retinol and 4.79% for ?-tocopherol. Developed extraction procedure was applied on 120 human breast milk samples. The separation of vitamins was completed using advantages of a monolithic column which accomplished demands of acceleration made by modern bio-analytical HPLC methodology. The analytes of interest were detected by diode-array detector at wavelengths 325 nm for retinol and 290 nm for ?-tocopherol. PMID:22483891

Kašparová, Markéta; Plíšek, Ji?í; Solichová, Dagmar; Kr?mová, Lenka; Ku?erová, Barbora; Hronek, Miloslav; Solich, Petr

2012-05-15

316

Amplification of FGF-related genes in human tumors: possible involvement of HST in breast carcinomas.  

PubMed

In order to document a possible involvement of structural alterations of FGF (Fibroblast Growth Factor)-like genes in human oncogenesis, we have screened a large series of human tumors for amplification of five FGF-related genes (Basic-FGF, INT2, HST, FGF5 and FGF6). None of 37 hematopoietic neoplasms, one out of 13 melanomas (8%), three out of 43 bladder tumors (7%) and 41 out of 238 breast carcinomas (17%) contained amplified FGF-related sequences, namely HST and INT2. Only these two genes, both located on band q13 of chromosome 11 have been found amplified. In all cases they were co-amplified and in only one instance did amplification extend to the ETS1 locus at position 11q23. INT2 and HST RNA could be evidenced by RNA/RNA in situ hybridization in breast carcinomas. Our results indicate a correlation between RNA expression and gene amplification in the case of HST but not of INT2. Although evaluation of the clinical significance of HST amplification and expression must await long-term follow-up of the patients, we suggest that HST gene product could play a role in development and/or progression of human breast cancer. PMID:2474139

Theillet, C; Le Roy, X; De Lapeyrière, O; Grosgeorges, J; Adnane, J; Raynaud, S D; Simony-Lafontaine, J; Goldfarb, M; Escot, C; Birnbaum, D

1989-07-01

317

Can rye intake decrease risk of human breast cancer?  

PubMed Central

Background Rye contains more fibre and bioactive compounds than other cereals used for bread production. The fibre and compounds of the fibre complex could provide protection against breast cancer (BC). Objective To review the evidence and theoretical background for a role of rye and some of its components in the prevention of BC. Design A short review based to a great extent on the work by scientists in the Nordic countries. Results Some of the possible mechanisms by which the fibre complex could reduce BC risk are presented. The fibre through its effect on fermentation increases esterification of bile acids reducing toxicity of the free bile acids and is involved in the production of butyrate with potential anticancer effects including BC. The fibre reduces the enterohepatic circulation of the oestrogens leading to lower plasma oestrogen concentrations. The fibre complex contains bioactive compounds such as lignans and alkylresorcinols that are antioxidative and potentially anticarcinogenic. In addition, vitamins, minerals, and phytic acid in rye may provide protection against BC. Conclusion Rye products made from wholegrain rye flour are likely to contribute to reduced BC risk. PMID:21311613

Adlercreutz, Herman

2010-01-01

318

Effects of estradiol and medroxyprogesterone acetate on morphology, proliferation and apoptosis of human breast tissue in organ cultures  

PubMed Central

Background Human breast tissue undergoes phases of proliferation, differentiation and regression regulated by changes of the levels of circulating sex hormones during the menstrual cycle or aging. Ovarian hormones also likely play a key role in the etiology and biology of breast cancer. Reports concerning the proliferative effects of steroid hormones on the normal epithelium of human breast have been conflicting. Some studies have shown that steroid hormones may predispose breast epithelial cells to malignant changes by stimulating their proliferation, which is known to be regulated tightly by stromal cells. The aim of this study was to investigate the effects of 17?-estradiol and medroxyprogesterone acetate on proliferation, apoptosis, expression of differentiation markers and steroid hormone receptors in breast epithelium using an in vitro model of freshly isolated human breast tissue, in which a proper interaction of breast epithelium and stroma has been maintained. Methods Human breast tissues were obtained from women undergoing surgery for breast tumours. Peritumoral tissues were excised and explants were cultured for 3 weeks in medium supplemented with E2 or MPA or with E2+MPA. Endpoints included histopathological, histomorphometric and immunohistochemical assessment of the breast explants. Results Culture of breast explants for 14 or 21 days with steroid hormones increased proliferative activity and the thickness of acinar and ductal epithelium. E2-treatment led to hyperplastic epithelial morphology, MPA to hypersecretory single-layered epithelium and E2+MPA to multilayered but organised epithelium. The proliferative response to E2 in comparison to control (p < 0.001) was more pronounced than to MPA (p < 0.05) or E2+MPA (p < 0.05) at 7 and 14 days for Ki-67 and PCNA. E2 treatment also decreased the proportion of apoptotic cells after 7 (p < 0.01) and 14 (p < 0.01) days. In addition, the relative number of ER?, ER? and PR positive epithelial cells was decreased by all hormonal treatments. Conclusion Organ culture system provides a model for studying the direct effects of steroid hormones and their analogues on postmenopausal human breast tissue. Addition of E2 or MPA or E2+MPA to breast explants caused characteristic changes in morphology, stimulated epithelial proliferation, lowered apoptosis ratio and decreased the relative number of epithelial cells expressing ER?, ER? and PR. PMID:17044944

Eigeliene, Natalija; Harkonen, Pirkko; Erkkola, Risto

2006-01-01

319

Phosphorylated and sumoylation-deficient progesterone receptors drive proliferative gene signatures during breast cancer progression  

PubMed Central

Introduction Progesterone receptors (PR) are emerging as important breast cancer drivers. Phosphorylation events common to breast cancer cells impact PR transcriptional activity, in part by direct phosphorylation. PR-B but not PR-A isoforms are phosphorylated on Ser294 by mitogen activated protein kinase (MAPK) and cyclin dependent kinase 2 (CDK2). Phospho-Ser294 PRs are resistant to ligand-dependent Lys388 SUMOylation (that is, a repressive modification). Antagonism of PR small ubiquitin-like modifier (SUMO)ylation by mitogenic protein kinases suggests a mechanism for derepression (that is, transcriptional activation) of target genes. As a broad range of PR protein expression is observed clinically, a PR gene signature would provide a valuable marker of PR contribution to early breast cancer progression. Methods Global gene expression patterns were measured in T47D and MCF-7 breast cancer cells expressing either wild-type (SUMOylation-capable) or K388R (SUMOylation-deficient) PRs and subjected to pathway analysis. Gene sets were validated by RT-qPCR. Recruitment of coregulators and histone methylation levels were determined by chromatin immunoprecipitation. Changes in cell proliferation and survival were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and western blotting. Finally, human breast tumor cohort datasets were probed to identify PR-associated gene signatures; metagene analysis was employed to define survival rates in patients whose tumors express a PR gene signature. Results 'SUMO-sensitive' PR target genes primarily include genes required for proliferative and pro-survival signaling. DeSUMOylated K388R receptors are preferentially recruited to enhancer regions of derepressed genes (that is, MSX2, RGS2, MAP1A, and PDK4) with the steroid receptor coactivator, CREB-(cAMP-response element-binding protein)-binding protein (CBP), and mixed lineage leukemia 2 (MLL2), a histone methyltransferase mediator of nucleosome remodeling. PR SUMOylation blocks these events, suggesting that SUMO modification of PR prevents interactions with mediators of early chromatin remodeling at 'closed' enhancer regions. SUMO-deficient (phospho-Ser294) PR gene signatures are significantly associated with human epidermal growth factor 2 (ERBB2)-positive luminal breast tumors and predictive of early metastasis and shortened survival. Treatment with antiprogestin or MEK inhibitor abrogated expression of SUMO-sensitive PR target-genes and inhibited proliferation in BT-474 (estrogen receptor (ER)+/PR+/ERBB2+) breast cancer cells. Conclusions We conclude that reversible PR SUMOylation/deSUMOylation profoundly alters target gene selection in breast cancer cells. Phosphorylation-induced PR deSUMOylation favors a permissive chromatin environment via recruitment of CBP and MLL2. Patients whose ER+/PR+ tumors are driven by hyperactive (that is, derepressed) phospho-PRs may benefit from endocrine (antiestrogen) therapies that contain an antiprogestin. PMID:22697792

2012-01-01

320

Beta-adrenergic and arachidonic acid-mediated growth regulation of human breast cancer cell lines.  

PubMed

Adenocarcinoma of the mammary gland is the leading type of cancer in women. Among these breast cancers those that are estrogen-responsive respond well to existing therapeutic regimens while estrogen non-responsive cancers metastasize widely, demonstrate a high relapse rate, and respond poorly to therapy. Over-expression of the arachidonic acid-metabolizing enzymes cyclooxygenase-2 and lypoxygenases is frequently observed in breast cancer, particularly the non-estrogen-responsive type, suggesting a role of the arachidonic acid (AA) cascade in the growth regulation of these malignancies. Adenocarcinomas of the lungs, pancreas and colon also frequently over-express AA-metabolizing enzymes, and recent evidence suggests that the growth-regulating AA-cascade in these malignancies is under beta-adrenergic control. Our current experiments have therefore tested the hypothesis that in analogy to these findings adenocarcinomas of the breast are also regulated by beta-adrenergic receptors via stimulation of the AA-cascade. Analysis of DNA synthesis by [3H]-thymidine incorporation assays in three estrogen-responsive and three estrogen non-responsive cell lines derived from human breast cancers demonstrated a significant reduction in DNA synthesis by beta-blockers and inhibitors of cyclooxygenase or lipoxygenases in all cell lines. Analysis of AA-release in one of the most responsive cell lines demonstrated a time-dependent increase in AA-release in response to the beta-adrenergic agonist isoproterenol. Analysis by RT-PCR revealed expression of beta2-adrenergic receptors in all cell lines whereas beta1-adrenergic receptors were not found in two of the estrogen non-responsive cell lines. Our data suggest that a significant subset of human breast cancers is under control of beta-adrenergic receptors via stimulation of the AA-cascade. These findings open up novel avenues for the prevention and clinical management of breast cancer, particularly the non-estrogen-responsive types. Moreover, our findings suggest that cardiovascular disease and adenocarcinomas in a variety of organ systems, including the breast may share common risk factors and benefit from similar preventive and treatment strategies. PMID:12063562

Cakir, Y; Plummer, H K; Tithof, P K; Schuller, H M

2002-07-01

321

Induction of cell death in antiestrogen resistant human breast cancer cells by the protein kinase CK2 inhibitor DMAT.  

PubMed

Protein kinase CK2 is involved in cell proliferation and survival, and found overexpressed in virtually all types of human cancer, including breast cancer. We demonstrate that inhibition of CK2 with 2-dimethylamino-4,5,6,7-tetrabromo-benzimidazole (DMAT), a potent and specific CK2 inhibitor, results in caspase-mediated killing of human breast cancer cells with acquired resistance to antiestrogens, while DMAT fails to kill parental MCF-7 cells. The antiestrogen resistant breast cancer cells express reduced levels of Bcl-2 compared to MCF-7 cells. Reduced Bcl-2 protein level is also found in a tamoxifen resistant human breast tumor grown as a xenograft. We show that re-expression of Bcl-2 partially rescues antiestrogen resistant MCF-7 sublines from DMAT-induced cell death. In summary, our data suggest a novel role of CK2 in antiestrogen resistance. PMID:17629615

Yde, Christina Westmose; Frogne, Thomas; Lykkesfeldt, Anne E; Fichtner, Iduna; Issinger, Olaf-Georg; Stenvang, Jan

2007-10-28

322

Metastatic consequences of immune escape from NK cell cytotoxicity by human breast cancer stem cells.  

PubMed

Breast cancer stem-like cells (BCSC) are crucial for metastasis but the underlying mechanisms remain elusive. Here, we report that tumor-infiltrating natural killer (NK) cells failed to limit metastasis and were not associated with improved therapeutic outcome of BCSC-rich breast cancer. Primary BCSCs were resistant to cytotoxicity mediated by autologous/allogeneic NK cells due to reduced expression of MICA and MICB, two ligands for the stimulatory NK cell receptor NKG2D. Furthermore, the downregulation of MICA/MICB in BCSCs was mediated by aberrantly expressed oncogenic miR20a, which promoted the resistance of BCSC to NK cell cytotoxicity and resultant lung metastasis. The breast cancer cell differentiation-inducing agent, all-trans retinoic acid, restored the miR20a-MICA/MICB axis and sensitized BCSC to NK cell-mediated killing, thereby reducing immune escape-associated BCSC metastasis. Together, our findings reveal a novel mechanism for immune escape of human BCSC and identify the miR20a-MICA/MICB signaling axis as a therapeutic target to limit metastatic breast cancer. Cancer Res; 74(20); 5746-57. ©2014 AACR. PMID:25164008

Wang, Bin; Wang, Qiang; Wang, Zhe; Jiang, Jun; Yu, Shi-Cang; Ping, Yi-Fang; Yang, Jing; Xu, Sen-Lin; Ye, Xian-Zong; Xu, Chuan; Yang, Lang; Qian, Cheng; Wang, Ji Ming; Cui, You-Hong; Zhang, Xia; Bian, Xiu-Wu

2014-10-15

323

Cathepsin D and epidermal growth factor in human breast cyst fluid.  

PubMed Central

Cathespin D (Cath D) is a proteolytic enzyme secreted by human breast cancer cells with a growth promoting activity in vitro. In the present study, we measured Cath D and Epidermal Growth Factor/alpha Transforming Growth Factor (EGF/alpha-TGF) concentrations in the breast cyst fluid (BCF) of 43 patients with gross cystic disease of the breast. Both Cath D (median 2.45 pmoles mg-1 protein; range 0-4.84 vs 0.98 pmoles mg-1 protein; range 0-3.11) and EGF/alpha-TGF (28.71 ng mg-1 protein; range 7.05-50.63 vs 10.83 ng mg-1 protein; range 0.06-30.55) levels were higher in BCF of apocrine than flattened cysts (P less than 0.0005 and P less than 0.01, respectively). Premenopausal patients showed higher concentrations of Cath D (P less than 0.05) and EGF/alpha-TGF (P less than 0.05) than postmenopausal patients. A positive correlation was obtained between intracystic concentrations of Cath D and EGF/alpha-TGF (P less than 0.00001). The higher levels of Cath-D and EGF/alpha-TGF found in apocrine cysts could provide an explanation for the increased risk of subsequent breast cancer in women with this type of cyst. PMID:1931627

Scambia, G.; Benedetti Panici, P.; Ferrandina, G.; Battaglia, F.; Rossi, S.; Bellantone, R.; Crucitti, F.; Mancuso, S.

1991-01-01

324

Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro.  

PubMed

Radiotherapy is one of the most effective therapeutic strategies for breast cancer patients, although its efficacy may be reduced by intrinsic radiation resistance of cancer cells. Recent investigations demonstrate a link between cancer cell radio-resistance and activation of sphingosine kinase (SphK1), which plays a key role in the balance of lipid signaling molecules. Sphingosine kinase (SphK1) activity can alter the sphingosine-1-phosphate (S1P)/ceramide ratio leading to an imbalance in the sphingolipid rheostat. Fingolimod (FTY720) is a novel sphingosine analog and a potent immunosuppressive drug that acts as a SphK1 antagonist, inhibits the growth, and induces apoptosis in different human cancer cell lines. We sought to investigate the in vitro radiosensitizing effects of FTY720 on the MDA-MB-361 breast cancer cell line and to assess the effects elicited by radiation and FTY720 combined treatments. We found that FTY720 significantly increased anti-proliferative and pro-apoptotic effects induced by a single dose of ionizing radiation while causing autophagosome accumulation. At the molecular level, FTY720 significantly potentiated radiation effects on perturbation of signaling pathways involved in regulation of cell cycle and apoptosis, such as PI3K/AKT and MAPK. In conclusion, our data highlight a potent radiosensitizing effect of FTY720 on breast cancer cells and provide the basis of novel therapeutic strategies for breast cancer treatment. PMID:24657936

Marvaso, Giulia; Barone, Agnese; Amodio, Nicola; Raimondi, Lavinia; Agosti, Valter; Altomare, Emanuela; Scotti, Valerio; Lombardi, Angela; Bianco, Roberto; Bianco, Cataldo; Caraglia, Michele; Tassone, Pierfrancesco; Tagliaferri, Pierosandro

2014-06-01

325

Identification of Prognostic Molecular Features in the Reactive Stroma of Human Breast and Prostate Cancer  

PubMed Central

Primary tumor growth induces host tissue responses that are believed to support and promote tumor progression. Identification of the molecular characteristics of the tumor microenvironment and elucidation of its crosstalk with tumor cells may therefore be crucial for improving our understanding of the processes implicated in cancer progression, identifying potential therapeutic targets, and uncovering stromal gene expression signatures that may predict clinical outcome. A key issue to resolve, therefore, is whether the stromal response to tumor growth is largely a generic phenomenon, irrespective of the tumor type or whether the response reflects tumor-specific properties. To address similarity or distinction of stromal gene expression changes during cancer progression, oligonucleotide-based Affymetrix microarray technology was used to compare the transcriptomes of laser-microdissected stromal cells derived from invasive human breast and prostate carcinoma. Invasive breast and prostate cancer-associated stroma was observed to display distinct transcriptomes, with a limited number of shared genes. Interestingly, both breast and prostate tumor-specific dysregulated stromal genes were observed to cluster breast and prostate cancer patients, respectively, into two distinct groups with statistically different clinical outcomes. By contrast, a gene signature that was common to the reactive stroma of both tumor types did not have survival predictive value. Univariate Cox analysis identified genes whose expression level was most strongly associated with patient survival. Taken together, these observations suggest that the tumor microenvironment displays distinct features according to the tumor type that provides survival-predictive value. PMID:21611158

Provero, Paolo; Fusco, Carlo; Delorenzi, Mauro; Stehle, Jean-Christophe; Stamenkovic, Ivan

2011-01-01

326

Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts.  

PubMed

Overexpression of colony-stimulating factor-1 (CSF-1) and its receptor in breast cancer is correlated with poor prognosis. Based on the hypothesis that blockade of CSF-1 would be beneficial in breast cancer treatment, we developed a murinized, polyethylene glycol-linked antigen-binding fragment (Fab) against mouse (host) CSF-1 (anti-CSF-1 Fab). Mice bearing human, chemoresistant MCF-7 breast cancer xenografts were treated with combination chemotherapy (CMF: cyclophosphamide, methotrexate, 5-fluorouracil; cycled twice i.p.), anti-CSF-1 Fab (i.p., cycled every 3 days for 14 days), combined CMF and anti-CSF-1 Fab, or with Ringer's solution as a control. Anti-CSF-1 Fab alone suppressed tissue CSF-1 and retarded tumor growth by 40%. Importantly, in combination with CMF, anti-CSF-1 Fab reversed chemoresistance of MCF-7 xenografts, suppressing tumor development by 56%, down-regulating expression of the chemoresistance genes breast cancer-related protein, multidrug resistance gene 1, and glucosylceramide synthase, and prolonging survival significantly. Combined treatment also reduced angiogenesis and macrophage recruitment and down-regulated tumor matrix metalloproteinase-2 (MMP-2) and MMP-12 expression. These studies support the paradigm of CSF-1 blockade in the treatment of solid tumors and show that anti-CSF-1 antibodies are potential therapeutic agents for the treatment of mammary cancer. PMID:16618760

Paulus, Patrick; Stanley, E Richard; Schäfer, Romana; Abraham, Dietmar; Aharinejad, Seyedhossein

2006-04-15

327

Study of human breast tissues biochemistry by FT-Raman spectroscopy  

NASA Astrophysics Data System (ADS)

In this work we employ the Fourier Transform Raman Spectroscopy to study the human breast tissues, both normal and pathological. In the present study we analyze 194 Raman spectra from breast tissues that were separated into 9 groups according to their corresponding histopathological diagnosis, which are as follows: Normal breast tissue, Fibrocystic condition, In Situ Duct Carcinoma, In Situ Duct Carcinoma with Necrosis, Infiltrating Duct Carcinoma, Infiltrating Duct Inflammatory Carcinoma, Infiltrating Duct Medullar Carcinoma, Infiltrating Duct Colloid Carcinoma, and Infiltrating Lobule Carcinoma. We found a strong lipids Raman band, and this structure was identified as abundant in the normal breast tissue spectra. The primary structure of proteins was identified through the shift of the amine acids bands. The identification of the secondary structure of proteins occurred through the peptide bands (Amide I and Amide III). In relation to the carbohydrates, the spectra of duct infiltrating colloid carcinoma, fibrocystic condition, and infiltrating duct carcinoma have been compared and identified. We observed an increase in the intensity of the 800-1200 cm -1 spectral region. This fact could indicate the presence of liquid cystic. We also notice alterations in the peaks in the region of 500 to 600 cm -1 and 2000 to 2100 cm -1 that may suggest changes in the nucleic acids of the cells.

Bitar, Renata A.; Jara, Walter Andres A.; Netto, Mário M.; Martinho, Herculano; Ramalho, Leandra Náira Z.; Martin, Airton A.

2006-02-01

328

A second generation of physical anthropomorphic 3D breast phantoms based on human subject data  

NASA Astrophysics Data System (ADS)

Previous fabrication of anthropomorphic breast phantoms has demonstrated their viability as a model for 2D (mammography) and 3D (tomosynthesis) breast imaging systems. Further development of these models will be essential for the evaluation of breast x-ray systems. There is also the potential to use them as the ground truth in virtual clinical trials. The first generation of phantoms was segmented from human subject dedicated breast computed tomography data and fabricated into physical models using highresolution 3D printing. Two variations were made. The first was a multi-material model (doublet) printed with two photopolymers to represent glandular and adipose tissues with the greatest physical contrast available, mimicking 75% and 35% glandular tissue. The second model was printed with a single 75% glandular equivalent photopolymer (singlet) to represent glandular tissue, which can be filled independently with an adipose-equivalent material such as oil. For this study, we have focused on improving the latter, the singlet phantom. First, the temporary oil filler has been replaced with a permanent adipose-equivalent urethane-based polymer. This offers more realistic contrast as compared to the multi-material approach at the expense of air bubbles and pockets that form during the filling process. Second, microcalcification clusters have been included in the singlet model via crushed eggshells, which have very similar chemical composition to calcifications in vivo. The results from these new prototypes demonstrate significant improvement over the first generation of anthropomorphic physical phantoms.

Nolte, Adam; Kiarashi, Nooshin; Samei, Ehsan; Segars, W. P.; Lo, Joseph Y.

2014-03-01

329

A human breast cell model of pre-invasive to invasive transition  

SciTech Connect

A crucial step in human breast cancer progression is the acquisition of invasiveness. There is a distinct lack of human cell culture models to study the transition from pre-invasive to invasive phenotype as it may occur 'spontaneously' in vivo. To delineate molecular alterations important for this transition, we isolated human breast epithelial cell lines that showed partial loss of tissue polarity in three-dimensional reconstituted-basement membrane cultures. These cells remained non-invasive; however, unlike their non-malignant counterparts, they exhibited a high propensity to acquire invasiveness through basement membrane in culture. The genomic aberrations and gene expression profiles of the cells in this model showed a high degree of similarity to primary breast tumor profiles. The xenograft tumors formed by the cell lines in three different microenvironments in nude mice displayed metaplastic phenotypes, including squamous and basal characteristics, with invasive cells exhibiting features of higher grade tumors. To find functionally significant changes in transition from pre-invasive to invasive phenotype, we performed attribute profile clustering analysis on the list of genes differentially expressed between pre-invasive and invasive cells. We found integral membrane proteins, transcription factors, kinases, transport molecules, and chemokines to be highly represented. In addition, expression of matrix metalloproteinases MMP-9,-13,-15,-17 was up regulated in the invasive cells. Using siRNA based approaches, we found these MMPs to be required for the invasive phenotype. This model provides a new tool for dissection of mechanisms by which pre-invasive breast cells could acquire invasiveness in a metaplastic context.

Bissell, Mina J; Rizki, Aylin; Weaver, Valerie M.; Lee, Sun-Young; Rozenberg, Gabriela I.; Chin, Koei; Myers, Connie A.; Bascom, Jamie L.; Mott, Joni D.; Semeiks, Jeremy R.; Grate, Leslie R.; Mian, I. Saira; Borowsky, Alexander D.; Jensen, Roy A.; Idowu, Michael O.; Chen, Fanqing; Chen, David J.; Petersen, Ole W.; Gray, Joe W.; Bissell, Mina J.

2008-03-10

330

BRCA1 mutation analysis of 41 human breast cancer cell lines reveals three new deleterious mutants.  

PubMed

Germ line mutations of the BRCA1 gene confer a high risk of breast cancer and ovarian cancer to female mutation carriers. The BRCA1 protein is involved in the regulation of DNA repair. How specific tumor-associated mutations affect the molecular function of BRCA1, however, awaits further elucidation. Cell lines that harbor BRCA1 gene mutations are invaluable tools for such functional studies. Up to now, the HCC1937 cell line was the only human breast cancer cell line with an identified BRCA1 mutation. In this study, we identified three other BRCA1 mutants from among 41 human breast cancer cell lines by sequencing of the complete coding sequence of BRCA1. Cell line MDA-MB-436 had the 5396 + 1G>A mutation in the splice donor site of exon 20. Cell line SUM149PT carried the 2288delT mutation and SUM1315MO2 carried the 185delAG mutation. All three mutations were accompanied by loss of the other BRCA1 allele. The 185delAG and 5396 + 1G>A mutations are both classified as pathogenic mutations. In contrast with wild-type cell lines, none of the BRCA1 mutants expressed nuclear BRCA1 proteins as detected with Ab-1 and Ab-2 anti-BRCA1 monoclonal antibodies. These three new human BRCA1 mutant cell lines thus seem to be representative breast cancer models that could aid in further unraveling of the function of BRCA1. PMID:16397213

Elstrodt, Fons; Hollestelle, Antoinette; Nagel, Jord H A; Gorin, Michael; Wasielewski, Marijke; van den Ouweland, Ans; Merajver, Sofia D; Ethier, Stephen P; Schutte, Mieke

2006-01-01

331

Phosphosulindac (OXT-328) selectively targets breast cancer stem cells in vitro and in human breast cancer xenografts  

PubMed Central

Pharmacological targeting of breast cancer stem cells (CSCs) is highly promising for the treatment of breast cancer, as the small population of CSCs appears responsible for tumor initiation and progression and also for resistance to conventional treatment. Here we report that the novel phosphosulindac (OXT-328, PS) selectively and effectively eliminates breast CSCs both in vitro and in vivo. PS reduced cell proliferaition and induced apoptosis in various breast CSCs. Breast CSCs are resistant to conventional cancer drugs but are sensitive to PS. Long-term treatment with PS of mixtures of cultured breast CSCs with breast cancer cells preferentially eliminated the CSCs. PS impaired the ability of CSCs to form mammospheres and markedly suppressed the expression of CSC-related genes. More importantly, PS prevented by half (p=0.06) the formation of tumors initiated by CSCs in immunodeficient mice, and inhibited by 83% (p<0.05) the growth of already formed breast cancer xenografts, reducing the proportion of CSCs in them. PS suppressed the Wnt/?-catenin pathway by stimulating the degradation of ?-catenin and its relocalization to the cell membrane; and also blocked the epithelial-mesenchymal transition (EMT) and the generation of breast CSCs. These results indicate that PS has a strong inhibitory effect against breast cancer, acting, at least in part, by targeting CSCs through a signaling mechanism involving Wnt signaling. PMID:22653497

Zhu, Caihua; Cheng, Ka-Wing; Ouyang, Nengtai; Huang, Liqun; Sun, Yu; Constantinides, Panayiotis P.; Rigas, Basil

2013-01-01

332

Utilization of human tissue in breast cancer research.  

PubMed

The use of human tissue, and material derived from such tissue, for research purposes is currently the subject of much debate. This debate needs to address several issues, including: the principle of abandonment; the distinction between identified and unidentified specimens; general versus specific informed consent; and, with the improvement in biotechnology and medical informatics, the design and security of research databases. The outcome of this debate will shape the way in which research studies using human biological materials are designed and executed. PMID:11250713

Prime, W; Sobel, M E; Herrington, C S

2000-01-01

333

Growth inhibitory activity of extracts and compounds from Cimicifuga species on human breast cancer cells  

PubMed Central

The purpose of this report is to explore the growth inhibitory effect of extracts and compounds from black cohosh and related Cimicifuga species on human breast cancer cells and to determine the nature of the active components. Black cohosh fractions enriched for triterpene glycosides and purified components from black cohosh and related Asian species were tested for growth inhibition of the ER? Her2 overexpressing human breast cancer cell line MDA-MB-453. Growth inhibitory activity was assayed using the Coulter Counter, MTT and colony formation assays. Results suggested that the growth inhibitory activity of black cohosh extracts appears to be related to their triterpene glycoside composition. The most potent Cimicifuga component tested was 25-acetyl-7,8-didehydrocimigenol 3-O-?-D-xylopyranoside, which has an acetyl group at position C-25. It had an IC50 of 3.2 µg/ml (5 µM) compared to7.2 µg/ml (12.1 µM) for the parent compound 7,8-didehydrocimigenol 3-O-?-D-xylopyranoside. Thus, the acetyl group at position C-25 enhances growth inhibitory activity. The purified triterpene glycoside actein (?-D-xylopyranoside), with an IC50 equal to 5.7 µg/ml (8.4 µM), exhibited activity comparable to cimigenol 3-O-?-D-xyloside. MCF7 (ER+Her2 low) cells transfected for Her2 are more sensitive than the parental MCF7 cells to the growth inhibitory effects of actein from black cohosh, indicating that Her2 plays a role in the action of actein. The effect of actein on Her2 overexpressing MDA-MB-453 and MCF7 (ER+Her2 low) human breast cancer cells was examined by fluorescent microscopy. Treatment with actein altered the distribution of actin filaments and induced apoptosis in these cells. These findings, coupled with our previous evidence that treatment with the triterpene glycoside actein induced a stress response and apoptosis in human breast cancer cells, suggest that compounds from Cimicifuga species may be useful in the prevention and treatment of human breast cancer. PMID:17980565

Einbond, Linda Saxe; Wen-Cai, Ye; He, Kan; Wu, Hsan-au; Cruz, Erica; Roller, Marc; Kronenberg, Fredi

2008-01-01

334

Perturbational Metabolic Profiling of Human Breast Cancer Cells  

EPA Science Inventory

A major goal of toxicity testing is to obtain toxicity data for protecting public health and the environment from adverse effects that may be caused by exposure to environmental agents in the air, water, soil and food. The current toxicological studies that target human health ef...

335

Induction of human breast cell carcinogenesis by triclocarban and intervention by curcumin  

PubMed Central

More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens and co-carcinogens. To identify co-carcinogens with abilities to induce cellular pre-malignancy, we studied the activity of triclocarban (TCC), an antimicrobial agent commonly used in household and personal care products. Here, we demonstrated, for the first time, that chronic exposure to TCC at physiologically-achievable nanomolar concentrations resulted in progressive carcinogenesis of human breast cells from non-cancerous to pre-malignant. Pre-malignant carcinogenesis was measured by increasingly-acquired cancer-associated properties of reduced dependence on growth factors, anchorage- independent growth and increased cell proliferation, without acquisition of cellular tumorigenicity. Long-term TCC exposure also induced constitutive activation of the Erk–Nox pathway and increases of reactive oxygen species (ROS) in cells. A single TCC exposure induced transient induction of the Erk–Nox pathway, ROS elevation, increased cell proliferation, and DNA damage in not only non-cancerous breast cells but also breast cancer cells. Using these constitutively- and transiently-induced changes as endpoints, we revealed that non-cytotoxic curcumin was effective in intervention of TCC-induced cellular pre-malignancy. Our results lead us to suggest that the co-carcinogenic potential of TCC should be seriously considered in epidemiological studies to reveal the significance of TCC in the development of sporadic breast cancer. Using TCC-induced transient and constitutive endpoints as targets will likely help identify non-cytotoxic preventive agents, such as curcumin, effective in suppressing TCC-induced cellular pre-malignancy. PMID:23942114

Sood, Shilpa; Choudhary, Shambhunath; Wang, Hwa-Chain Robert

2013-01-01

336

Induction of human breast cell carcinogenesis by triclocarban and intervention by curcumin.  

PubMed

More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens and co-carcinogens. To identify co-carcinogens with abilities to induce cellular pre-malignancy, we studied the activity of triclocarban (TCC), an antimicrobial agent commonly used in household and personal care products. Here, we demonstrated, for the first time, that chronic exposure to TCC at physiologically-achievable nanomolar concentrations resulted in progressive carcinogenesis of human breast cells from non-cancerous to pre-malignant. Pre-malignant carcinogenesis was measured by increasingly-acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth and increased cell proliferation, without acquisition of cellular tumorigenicity. Long-term TCC exposure also induced constitutive activation of the Erk-Nox pathway and increases of reactive oxygen species (ROS) in cells. A single TCC exposure induced transient induction of the Erk-Nox pathway, ROS elevation, increased cell proliferation, and DNA damage in not only non-cancerous breast cells but also breast cancer cells. Using these constitutively- and transiently-induced changes as endpoints, we revealed that non-cytotoxic curcumin was effective in intervention of TCC-induced cellular pre-malignancy. Our results lead us to suggest that the co-carcinogenic potential of TCC should be seriously considered in epidemiological studies to reveal the significance of TCC in the development of sporadic breast cancer. Using TCC-induced transient and constitutive endpoints as targets will likely help identify non-cytotoxic preventive agents, such as curcumin, effective in suppressing TCC-induced cellular pre-malignancy. PMID:23942114

Sood, Shilpa; Choudhary, Shambhunath; Wang, Hwa-Chain Robert

2013-09-01

337

Dracorhodin Perchlorate Induced Human Breast Cancer MCF-7 Apoptosis through Mitochondrial Pathways  

PubMed Central

Objective: Dracorhodin perchlorate (DP) was a synthetic analogue of the antimicrobial anthocyanin red pigment dracorhodin. It was reported that DP could induce apoptosis in human prostate cancer, human gastric tumor cells and human melanoma, but the cytotoxic effect of DP on human breast cancer was not investigated. This study would investigate whether DP was a candidate chemical of anti-human breast cancer. Methods: The MTT assay reflected the number of viable cells through measuring the activity of cellular enzymes. Phase contrast microscopy visualized cell morphology. Fluorescence microscopy detected nuclear fragmentation after Hoechst 33258 staining. Flowcytometric analysis of Annexin V-PI staining and Rodamine 123 staining was used to detect cell apoptosis and mitochondrial membrane potential (MMP). Real time PCR detected mRNA level. Western blot examined protein expression. Results: DP dose and time-dependently inhibited the growth of MCF-7 cells. DP inhibited MCF-7 cell growth through apoptosis. DP regulated the expression of Bcl-2 and Bax, which were mitochondrial pathway proteins, to decrease MMP, and DP promoted the transcription of Bax and inhibited Bcl-2. Apoptosis-inducing factor (AIF) and cytochrome c which localized in mitochondrial in physiological condition were released into cytoplasm when MMP was decreased. DP activated caspase-9, which was the downstream of mitochondrial pathway. Therefore DP decreased MMP to release AIF and cytochrome c into cytoplasm, further activating caspase 9, lastly led to apoptosis. Conclusion: Therefore DP was a candidate for anti-breast cancer, DP induced apoptosis of MCF-7 through mitochondrial pathway. PMID:23869191

Yu, Jing-hua; Zheng, Gui-bin; Liu, Chun-yu; Zhang, Li-ying; Gao, Hong-mei; Zhang, Ya-hong; Dai, Chun-yan; Huang, Lin; Meng, Xian-ying; Zhang, Wen-yan; Yu, Xiao-fang

2013-01-01

338

In Vitro Effects of Herbicides and Insecticides on Human Breast Cells  

PubMed Central

Numerous studies have indicated that the pesticides and herbicides used in agricultural processes in the United States and Europe may have detrimental effects upon human health. Many of these compounds have been indicated as potential endocrine and reproductive disruptors, although the studies have examined supraphysiological levels well above the US EPA safe levels for drinking water and have often examined these effects in “model” cell lines such as Chinese hamster ovary cells. We have now examined the cytotoxicity of more environmentally relevant concentrations of four herbicides, acetochlor, atrazine, cyanazine, and simazine, and two insecticides, chlorpyrifos and resmethrin, in three human breast cell lines. Interestingly, cytotoxicity was not observed in the estrogen-dependent MCF-7 mammary epithelial carcinoma cells; rather increases in cell viability were seen for some of the compounds at select concentrations. These results vary greatly from what was observed in the estrogen independent MDA-MB-231 breast cancer cells and the non-cancerous MCF-10A breast cells. This gives insight into how different tumors may respond to pesticide exposure and allows us to make more accurate conclusions about the potential cytotoxicity or, at times, stimulatory actions of these pesticides. PMID:23762632

Rich, Jessica D.; Gabriel, Seth M.; Schultz-Norton, Jennifer R.

2012-01-01

339

In vitro effects of herbicides and insecticides on human breast cells.  

PubMed

Numerous studies have indicated that the pesticides and herbicides used in agricultural processes in the United States and Europe may have detrimental effects upon human health. Many of these compounds have been indicated as potential endocrine and reproductive disruptors, although the studies have examined supraphysiological levels well above the US EPA safe levels for drinking water and have often examined these effects in "model" cell lines such as Chinese hamster ovary cells. We have now examined the cytotoxicity of more environmentally relevant concentrations of four herbicides, acetochlor, atrazine, cyanazine, and simazine, and two insecticides, chlorpyrifos and resmethrin, in three human breast cell lines. Interestingly, cytotoxicity was not observed in the estrogen-dependent MCF-7 mammary epithelial carcinoma cells; rather increases in cell viability were seen for some of the compounds at select concentrations. These results vary greatly from what was observed in the estrogen independent MDA-MB-231 breast cancer cells and the non-cancerous MCF-10A breast cells. This gives insight into how different tumors may respond to pesticide exposure and allows us to make more accurate conclusions about the potential cytotoxicity or, at times, stimulatory actions of these pesticides. PMID:23762632

Rich, Jessica D; Gabriel, Seth M; Schultz-Norton, Jennifer R

2012-01-01

340

PACE4 regulates proliferation, migration and invasion in human breast cancer MDA-MB-231 cells.  

PubMed

PACE4 is one of the proprotein convertases (PC) that participate in the post-translational activation of inactive proteins, leading to mature, biologically active proteins. The processing reactions occur in pairs of basic amino acids. PACE4 is an extracellular PC that binds to growth factors and several components of the extracellular matrix contributing to tumor progression. In the present study, the PACE4 gene was silenced by small interfering RNA (siRNA), and the knockdown human breast cancer MDA-MB-231 cells showed signi-ficantly reduced proliferation, migration and invasion rates. Flow cytometry analysis indicated that downregulation of PACE4 increases the percentage of cells arrested at the G0/G1 phase. Moreover, the expression of genes involved in cell growth, invasion and adhesion, i.e., IGF-2, MMP9 and MPZL2 was significantly decreased following siRNA?mediated silencing of PACE4. Taken together, these results indicate that PACE4 plays an important role in human breast cancer, and that it might represent a novel target for breast cancer therapy. PMID:25333574

Wang, Feifei; Wang, Lin; Pan, Jihong

2015-01-01

341

Early Results Using Sterilized Acellular Human Dermis (Neoform) in Post-Mastectomy Tissue Expander Breast Reconstruction.  

PubMed

ABSTRACT: Acellular dermal products play a beneficial role in immediate tissue expander breast reconstruction. They provide improved coverage and support in the lower pole, allowing the pectoralis muscle to drape over most of the expander and maximize lower pole expansion. Tissue incorporation is desired without any adverse affects on recovery. The purpose of this series is to evaluate the early safety and morbidity of preserved human allograft dermis sterilized using the Tutoplast(R) process.All patients who underwent tissue expander reconstruction with NeoForm(R) at Emory University Hospital between 6/07 and 4/08 were included in the series. Patient demographics, risk factors, surgical technique, early complications and outcomes were evaluated.Twenty-two consecutive patients were included, with a total of 31 breasts (bilateral n=9, left n=9, right n=4). The average age was 48 years (range: 31-71), with an average body mass index of 26.7 (range: 19-35). Fifteen patients had a diagnosis of invasive breast cancer and 7 patients had DCIS. Risk factors included hypertension n=5, history of smoking n=2, diabetes n=1, and post operative radiation therapy n=8. All reconstructions were immediate with lower pole tissue expanders. NeoForm was rehydrated for appropriately 3-5 minutes. It was sutured superiorly to the lower border of the pectoralis muscle and inferiorly to the inframammary fold. The 4x16 size was used in 18 breasts, and 6x16 cm in 13 breasts. Early post operative complications occurred in one patient with native mastectomy skin necrosis. All drains were removed by the third post-operative week. There were no cases with infection, foreign body reaction, rejection, seromas, or skin erythema. Tissue expansion was performed without any difficult. Expander removal and secondary implant insertion demonstrated adequate incorporation of the NeoForm in 16 patients. Encapsulation of the Neoform, infection or extrusion was not observed.Acellular dermal products have become a useful addition to tissue expander breast reconstruction. NeoForm was successfully used for lower pole coverage of the tissue expander in 31 immediate expander breast reconstructions. Good tissue incorporation was observed clinically and there were no post operative complications that could be related to the NeoForm. PMID:19342990

Losken, Albert

2009-03-23

342

Evaluating human cancer cell metastasis in zebrafish  

PubMed Central

Background In vivo metastasis assays have traditionally been performed in mice, but the process is inefficient and costly. However, since zebrafish do not develop an adaptive immune system until 14 days post-fertilization, human cancer cells can survive and metastasize when transplanted into zebrafish larvae. Despite isolated reports, there has been no systematic evaluation of the robustness of this system to date. Methods Individual cell lines were stained with CM-Dil and injected into the perivitelline space of 2-day old zebrafish larvae. After 2-4 days fish were imaged using confocal microscopy and the number of metastatic cells was determined using Fiji software. Results To determine whether zebrafish can faithfully report metastatic potential in human cancer cells, we injected a series of cells with different metastatic potential into the perivitelline space of 2 day old embryos. Using cells from breast, prostate, colon and pancreas we demonstrated that the degree of cell metastasis in fish is proportional to their invasion potential in vitro. Highly metastatic cells such as MDA231, DU145, SW620 and ASPC-1 are seen in the vasculature and throughout the body of the fish after only 24–48 hours. Importantly, cells that are not invasive in vitro such as T47D, LNCaP and HT29 do not metastasize in fish. Inactivation of JAK1/2 in fibrosarcoma cells leads to loss of invasion in vitro and metastasis in vivo, and in zebrafish these cells show limited spread throughout the zebrafish body compared with the highly metastatic parental cells. Further, knockdown of WASF3 in DU145 cells which leads to loss of invasion in vitro and metastasis in vivo also results in suppression of metastasis in zebrafish. In a cancer progression model involving normal MCF10A breast epithelial cells, the degree of invasion/metastasis in vitro and in mice is mirrored in zebrafish. Using a modified version of Fiji software, it is possible to quantify individual metastatic cells in the transparent larvae to correlate with invasion potential. We also demonstrate, using lung cancers, that the zebrafish model can evaluate the metastatic ability of cancer cells isolated from primary tumors. Conclusions The zebrafish model described here offers a rapid, robust, and inexpensive means of evaluating the metastatic potential of human cancer cells. Using this model it is possible to critically evaluate whether genetic manipulation of signaling pathways affects metastasis and whether primary tumors contain metastatic cells. PMID:24089705

2013-01-01

343

Differentiation of ex vivo human breast tissue using polarization-sensitive optical coherence tomography  

PubMed Central

Successful treatment of breast cancer typically requires surgical removal of the tumor. Optical coherence tomography (OCT) has been previously developed for real-time imaging of the surgical margin. However, it can be difficult to distinguish between normal stromal tissue and cancer tissue based on scattering intensity and structure alone. Polarization-sensitive optical coherence tomography (PS-OCT) is sensitive to form birefringence of biological tissue. We report on the development of a high-speed PS-OCT system and imaging of ex vivo human breast tissue, showing enhanced contrast between healthy and cancerous tissues based upon collagen content confirmed with corresponding histology. These results demonstrate the feasibility of using PS-OCT to supplement structural OCT as a possible method for intraoperative tumor margin evaluation. PMID:25360360

South, Fredrick A.; Chaney, Eric J.; Marjanovic, Marina; Adie, Steven G.; Boppart, Stephen A.

2014-01-01

344

Antenna applicator design for microwave imaging of the interior of human breasts  

NASA Astrophysics Data System (ADS)

In this paper we introduce a waveguide antenna applicator design intended to be placed on the surface or in close proximity to a human breast for imaging purposes. Hence, the antenna needs to be compact for easy placement. The design process is carefully carried out dividing the antenna applicator into separate parts, allowing closer analysis towards improved synthesis. A mode applicator antenna was concluded to be necessary, employing a TE10 mode type with minimized near-field and surface (Zennek) wave excitation. Numerical simulations have been used throughout and show that the proposed ridged waveguide antenna is capable of fulfilling the design requirements and the performance goals. Modelling has been carried out using a scenario with a simple breast model and confirms the applicator's capability.

Petrovi?, N.; Otterskog, M.; Risman, P. O.

2014-09-01

345

Effect of non-thermal atmospheric pressure plasma jet on human breast cancer cells  

NASA Astrophysics Data System (ADS)

Nowadays, Non-thermal plasma enjoy a wide range of applications in biomedical fields such as Sterilization, Wound healing, Cancer treatment and etc. The aim of this paper is to study the effect of non-thermal atmospheric pressure plasma jet on breast cancer (MCF-7) cells. In this regard the effect of plasma on death of the cancer cells are explored experimentally. The plasma in this discharge is created by pulsed dc high voltage power supply with repetition rate of several tens of kilohertz which led to the inductively coupled plasma. The pure helium gas were used for formation of the plasma jet. MTT assay were used for quantification of death cells. The results showed that the cells death rate increase with plasma exposure time. This study confirm that plasma jet have significant effect on treatment of human breast cancer cells.

Mirpour, Shahriar; Nikkhah, Maryam; Pirouzmand, Somaye; Ghomi, Hamid Reza

2012-10-01

346

Cancer Risk-Assessment of Radiation Damage in Ataxia Telangiectasia Heterozygous Human Breast Epithelial Cell Cultures  

NASA Technical Reports Server (NTRS)

This paper describes the study of the markers of cellular changes that are found during the onset of carcinogenesis. Several of the biological factors are markers of stress response, oncoprotein expression, and differentiation factors. Oxidative stress response agents such as heat shock proteins (HSPs) protect cells from oxidative stresses such as ionizing radiation. The onocoprotein HER-2/neu, a specific breast cancer marker, indicates early onset of cancer. Additional structural and morphogenetic markers of differentiation were considered in order to determine initial cellular changes at the initial onset of cancer. As an additional consideration, all-trans retinoic acid (RA), a differentiation agent, was considered because of its known role in regulating normal differentiation and inhibiting tumor proliferation via specific nuclear receptors. This paper discusses study and results of the preliminary analyses of gamma irradiation of AT heterozygous human breast epithelial cells (WH). Comparisons are also made of the effects various RA concentrations post-irradiation.

Applewhite, Lisa C.

2002-01-01

347

Differentiation of ex vivo human breast tissue using polarization-sensitive optical coherence tomography.  

PubMed

Successful treatment of breast cancer typically requires surgical removal of the tumor. Optical coherence tomography (OCT) has been previously developed for real-time imaging of the surgical margin. However, it can be difficult to distinguish between normal stromal tissue and cancer tissue based on scattering intensity and structure alone. Polarization-sensitive optical coherence tomography (PS-OCT) is sensitive to form birefringence of biological tissue. We report on the development of a high-speed PS-OCT system and imaging of ex vivo human breast tissue, showing enhanced contrast between healthy and cancerous tissues based upon collagen content confirmed with corresponding histology. These results demonstrate the feasibility of using PS-OCT to supplement structural OCT as a possible method for intraoperative tumor margin evaluation. PMID:25360360

South, Fredrick A; Chaney, Eric J; Marjanovic, Marina; Adie, Steven G; Boppart, Stephen A

2014-10-01

348

Copper, lead and zinc concentrations of human breast milk as affected by maternal dietary practices  

SciTech Connect

Maternal dietary practices have been found to affect the concentrations of some nutrients in human breast milk. Lead toxicity is a concern in young children. Lead, copper and zinc are thought to compete for intestinal absorption sites. The objective of the current project was to compare copper, lead and zinc contents of breast milk from practicing lacto-vegetarian and omnivore, lactating women at approximately four months post-partum. Analyses were done by atomic absorption spectrophotometry using a carbon rod attachment. Copper concentrations were higher in milk samples from lacto-ovo-vegetarians. Milk samples from the omnivores had the highest lead and zinc concentrations. Lead and copper concentrations in milk were negatively correlated. The higher zinc concentrations in the milk of the omnivore women may have been related to better utilization of zinc from meat than from plant food sources.

Umoren, J.; Kies, C.

1986-03-01

349

Targeting the Transforming Growth Factor-? pathway inhibits human basal-like breast cancer metastasis  

PubMed Central

Background Transforming Growth Factor ? (TGF-?) plays an important role in tumor invasion and metastasis. We set out to investigate the possible clinical utility of TGF-? antagonists in a human metastatic basal-like breast cancer model. We examined the effects of two types of the TGF-? pathway antagonists (1D11, a mouse monoclonal pan-TGF-? neutralizing antibody and LY2109761, a chemical inhibitor of TGF-? type I and II receptor kinases) on sublines of basal cell-like MDA-MB-231 human breast carcinoma cells that preferentially metastasize to lungs (4175TR, 4173) or bones (SCP2TR, SCP25TR, 2860TR, 3847TR). Results Both 1D11 and LY2109761 effectively blocked TGF-?-induced phosphorylation of receptor-associated Smads in all MDA-MB-231 subclones in vitro. Moreover, both antagonists inhibited TGF-? stimulated in vitro migration and invasiveness of MDA-MB-231 subclones, indicating that these processes are partly driven by TGF-?. In addition, both antagonists significantly reduced the metastatic burden to either lungs or bones in vivo, seemingly independently of intrinsic differences between the individual tumor cell clones. Besides inhibiting metastasis in a tumor cell autonomous manner, the TGF-? antagonists inhibited angiogenesis associated with lung metastases and osteoclast number and activity associated with lytic bone metastases. In aggregate, these studies support the notion that TGF-? plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-? signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-? pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer. Conclusions In aggregate, these studies support the notion that TGF-? plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-? signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-? pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer. PMID:20504320

2010-01-01

350

Development and evaluation of an anchorage-independent agar-based clonal assay for human primary breast carcinoma cells  

SciTech Connect

The development and evaluation of an anchorage-independent clonal cytotoxic assay for primary human breast carcinoma cells is described in this thesis. This assay was developed in three stages which include: (1) the optimization of the production of a monodispersed cell suspension from solid breast carcinomas, (2) the systematic development of a growth medium for the clonal growth of these cells, and (3) the adaptation of these methods for use in the quantitation of cytotoxicity. The results of these studies indicated that hydrocortisone, fetal bovine serum and red blood cells stimulated the clonal growth of breast carcinoma cells. The optimal concentrations of these three factors were simultaneously determined using response surface methodology. These culture conditions were then used to develop radiation-cytotoxicity assays for both primary and recurrent breast carcinomas. The methodology developed and evaluated in this thesis may be useful to: (1) study the biology and radiobiology of human breast cancer, (2) customize the treatment of individual breast cancer patients, and (3) identify and/or develop new drugs and/or other treatment modalities for breast cancer.

Besch, G.J.

1985-01-01

351

FOXM1 promotes the epithelial to mesenchymal transition by stimulating the transcription of Slug in human breast cancer.  

PubMed

The Forkhead Box M1 (FOXM1) transcription factor is involved in tumorigenesis and tumor progression in multiple human carcinomas. In this study, we found that FOXM1 promoted the epithelial to mesenchymal transition (EMT) in human breast cancer. We observed a strong correlation between the expression levels of FOXM1 and the mesenchymal phenotype. Knockdown of FOXM1 inhibited the mesenchymal phenotype, whereas stable overexpression of FOXM1 induced EMT in breast cancer cells. FOXM1 was found to endogenously bind to and stimulate the promoter of Slug that is crucial for EMT progression. The knockdown of Slug abolished the EMT-inducing function of FOXM1. The stable overexpression of FOXM1 promoted metastasis of breast cancer cells in vivo. This study confirmed that FOXM1 promoted EMT in breast cancer cells by stimulating the transcription of EMT-related genes such as Slug. PMID:23856032

Yang, Chao; Chen, Hui; Tan, Guixiang; Gao, Wei; Cheng, Liang; Jiang, Xia; Yu, Li; Tan, Yongjun

2013-10-28

352

Human Breast Progenitor Cell Numbers Are Regulated by WNT and TBX3  

PubMed Central

Background Although human breast development is mediated by hormonal and non-hormonal means, the mechanisms that regulate breast progenitor cell activity remain to be clarified. This limited understanding of breast progenitor cells has been due in part to the lack of appropriate model systems to detect and characterize their properties. Methods To examine the effects of WNT signaling and TBX3 expression on progenitor activity in the breast, primary human mammary epithelial cells (MEC) were isolated from reduction mammoplasty tissues and transduced with lentivirus to overexpress WNT1 or TBX3 or reduce expression of their cognate receptors using shRNA. Changes in progenitor activity were quantified using characterized assays. We identified WNT family members expressed by cell populations within the epithelium and assessed alterations in expression of WNT family ligands by MECs in response to TBX3 overexpression and treatment with estrogen and progesterone. Results Growth of MECs on collagen gels resulted in the formation of distinct luminal acinar and basal ductal colonies. Overexpression of TBX3 in MECs resulted in increased ductal colonies, while shTBX3 expression diminished both colony types. Increased WNT1 expression led to enhanced acinar colony formation, shLRP6 decreased both types of colonies. Estrogen stimulated the formation of acinar colonies in control MEC, but not shLRP6 MEC. Formation of ductal colonies was enhanced in response to progesterone. However, while shLRP6 decreased MEC responsiveness to progesterone, shTBX3 expression did not alter this response. Conclusions We identified two phenotypically distinguishable lineage-committed progenitor cells that contribute to different structural elements and are regulated via hormonal and non-hormonal mechanisms. WNT signaling regulates both types of progenitor activity. Progesterone favors the expansion of ductal progenitor cells, while estrogen stimulates the expansion of acinar progenitor cells. Paracrine WNT signaling is stimulated by estrogen and progesterone, while autocrine WNT signaling is induced by the embryonic T-box transcription factor TBX3. PMID:25350852

Arendt, Lisa M.; St. Laurent, Jessica; Wronski, Ania; Caballero, Silvia; Lyle, Stephen R.; Naber, Stephen P.; Kuperwasser, Charlotte

2014-01-01

353

Tranilast enhances the anti-tumor effects of tamoxifen on human breast cancer cells in vitro  

PubMed Central

Background Tamoxifen is the most widely used anti-estrogen for the treatment of breast cancer. Studies show that the combination therapy with other substances that helps the activity of tamoxifen. The objective of this study was to evaluate the effect of tamoxifen when used in combination with tranilast on human breast cancer cells. Results Two MCF-7 and MDA-MB-231 human breast cancer cell lines were treated with tamoxifen and/or tranilast. The cell viability and cytotoxicity was assessed using MTT and LDH assays; the apoptotic effects were examined by TUNEL assay, acridine orange/ethidium bromide staining and DNA laddering, also the expression levels of bax and bcl-2 genes were detected by real-time RT-PCR. The mRNA expression of TGF-? ligands and receptors examined using real-time RT-PCR and TGF-?1 protein secretion levels were also evaluated by ELISA assay. Inhibitory effect of these drugs on invasion and metastasis were tested by wound healing and matrigel invasion assay. We found that combination of these drugs led to a marked increase in growth and proliferation inhibition compared to either agent alone. Furthermore, bax and bcl-2 affected by tamoxifen and/or tranilast and resulted in a significant increase in bax and decrease in bcl-2 mRNA expression. In addition, treatment with tamoxifen and/or tranilast resulted in significant decreased in TGF-?1, 2, 3, TGF-?RI and II mRNA and TGF-?1 protein levels while TGF-?RIII mRNA level was increased and invasion was also inhibited. Conclusions These findings indicate that tranilast, by synergistic effect, enhances the activity of tamoxifen and the TGF-? pathway is a target for this combination therapy, therefore; we propose that this combined treatment may be suitable selection in prevention of breast cancer. PMID:24143895

2013-01-01

354

Cytotoxic Effect of Conjugates of Doxorubicin and Human Chorionic Gonadotropin (hCG) in Breast Cancer Cells  

Microsoft Academic Search

Cytotoxic activity of drug conjugates of human chorionic gonadotropin (hCG) and doxorubicin alone was investigated compared to doxorubicin in breast cancer cells with and without expression of hCG receptors. Expression of hCG receptor was determined in MCF-7 and MB231 breast cancer cell line using a multiplex nested rt-PCR approach. The entire sequence of mRNA encoding for hCG receptor was detected

Gerhard Gebauer; Tanja Fehm; Eberhard P. Beck; Alexander Berkholz; Peter Licht; Wolfram Jäger

2003-01-01

355

MEK inhibition leads to lysosome-mediated Na+/I- symporter protein degradation in human breast cancer cells.  

PubMed

The Na(+)/I(-) symporter (NIS (SLC5A5)) is a transmembrane glycoprotein that mediates active iodide uptake into thyroid follicular cells. NIS-mediated iodide uptake in thyroid cells is the basis for targeted radionuclide imaging and treatment of differentiated thyroid carcinomas and their metastases. Furthermore, NIS is expressed in many human breast tumors but not in normal non-lactating breast tissue, suggesting that NIS-mediated radionuclide uptake may also allow the imaging and targeted therapy of breast cancer. However, functional cell surface NIS expression is often low in breast cancer, making it important to uncover signaling pathways that modulate NIS expression at multiple levels, from gene transcription to posttranslational processing and cell surface trafficking. In this study, we investigated NIS regulation in breast cancer by MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) signaling, an important cell signaling pathway involved in oncogenic transformation. We found that MEK inhibition decreased NIS protein levels in all-trans retinoic acid/hydrocortisone-treated MCF-7 cells as well as human breast cancer cells expressing exogenous NIS. The decrease in NIS protein levels by MEK inhibition was not accompanied by a decrease in NIS mRNA or a decrease in NIS mRNA export from the nucleus to the cytoplasm. NIS protein degradation upon MEK inhibition was prevented by lysosome inhibitors but not by proteasome inhibitors. Interestingly, NIS protein level was correlated with MEK/ERK activation in human breast tumors from a tissue microarray. Taken together, MEK activation appears to play an important role in maintaining NIS protein stability in human breast cancers. PMID:23404856

Zhang, Zhaoxia; Beyer, Sasha; Jhiang, Sissy M

2013-04-01

356

Growth inhibition and growth stimulation by estradiol of estrogen receptor transfected human breast epithelial cell lines involve different pathways  

Microsoft Academic Search

Epidermal growth factor (EGF) and estradiol (E2) are important mitogens in breast epithelial cells, and expression of epidermal growth factor receptor (EGFR) and estrogen receptor (ER) is often inversely correlated in human breast cancer cells. Stable transfection of ER-negative cells with ER cDNA is not sufficient to restore E2-mediated growth stimulation, on the contrary, E2 often inhibits growth of ER-transfected

Betina K. Lundholt; Per Briand; Anne E. Lykkesfeldt

2001-01-01

357

Evaluation of chemopreventive and cytotoxic effect of lemon seed extracts on human breast cancer (MCF7) cells  

Microsoft Academic Search

Extracts from lemon seed were investigated for the radical scavenging activity and apoptotic effects in human breast adenocarcinoma (MCF-7) cells and non-malignant breast (MCF-12F) cells for the first time. Defatted seed powder was successively extracted with ethyl acetate (EtOAc), acetone, methanol (MeOH), and MeOH:water (80:20) and the chemical constituents were identified and quantified by LC-MS and HPLC analysis. The highest

Jinhee Kim; Guddadarangavvanahally; K. Jayaprakasha; Ram M. Uckoo; Bhimanagouda S. Patil

358

MEK Inhibition Leads To Lysosome-Mediated Na+/I- Symporter Protein Degradation In Human Breast Cancer Cells  

PubMed Central

The Na+/I- symporter (NIS) is a transmembrane glycoprotein that mediates active iodide uptake into thyroid follicular cells. NIS-mediated iodide uptake in thyroid cells is the basis for targeted radionuclide imaging and treatment of differentiated thyroid carcinomas and their metastases. Furthermore, NIS is expressed in many human breast tumors but not in normal non-lactating breast tissue, suggesting that NIS-mediated radionuclide uptake may also allow the imaging and targeted therapy of breast cancer. However, functional cell surface NIS expression is often low in breast cancer, making it important to uncover signaling pathways that modulate NIS expression at multiple levels, from gene transcription to post-translational processing and cell surface trafficking. In this study, we investigated NIS regulation in breast cancer by MEK (MAPK/ERK kinase) signaling, an important cell signaling pathway involved in oncogenic transformation. We found that MEK inhibition decreased NIS protein levels in all-trans retinoic acid (tRA)/hydrocortisone treated MCF-7 cells as well as human breast cancer cells expressing exogenous NIS. The decrease in NIS protein levels by MEK inhibition was not accompanied by a decrease in NIS mRNA or a decrease in NIS mRNA export from the nucleus to the cytoplasm. NIS protein degradation upon MEK inhibition was prevented by lysosome inhibitors, but not by proteasome inhibitors. Interestingly, NIS protein level was correlated with MEK/ERK activation in human breast tumors from a tissue microarray. Taken together, MEK activation appears to play an important role in maintaining NIS protein stability in human breast cancers. PMID:23404856

Zhang, Zhaoxia; Beyer, Sasha; Jhiang, Sissy M

2013-01-01

359

High TIMM17A expression is associated with adverse pathological and clinical outcomes in human breast cancer  

Microsoft Academic Search

Background  Mitochondrial dysfunction can be associated with genomic instability and has been implicated in the pathogenesis of several\\u000a human malignancies, including breast cancer (BC). The mitochondrial protein, translocase of inner mitochondrial membrane 17\\u000a homolog A (TIMM17A) contributes to a pre-protein import complex, essential for mitochondrial function. In this study, TIMM17A\\u000a mRNA expression was evaluated in benign and malignant breast tissues and

Mohamed Salhab; Neill Patani; Wen Jiang; Kefah Mokbel

360

Quercetin Inhibits Heat Shock Protein Induction but Not Heat Shock Factor DNA-Binding in Human Breast Carcinoma Cells  

Microsoft Academic Search

The flavonoid quercetin inhibits the heat-induced synthesis of heat shock proteins (hsps) in a variety of cell lines. To determine whether quercetin could inhibit hsp expression in breast cancer cells, we used the human breast cancer cell line, MDA-MB-231. Treatment of these cells with quercetin decreased the heat-induced synthesis of hsp27 and hsp70. However, inhibition of hsp expression did not

R. K. Hansen; S. Oesterreich; P. Lemieux; K. D. Sarge; S. A. W. Fuqua

1997-01-01

361

Dietary Organic Isothiocyanates Are Cytotoxic in Human Breast Cancer MCF7 and Mammary Epithelial MCF12A Cell Lines  

Microsoft Academic Search

Organic isothiocyanates (ITCs) are dietary components present in cruciferous vegetables. The purpose of this investigation was to examine the cytotoxicity of 1-naphthyl isothiocyanate (NITC), benzyl isothiocyanate (BITC), b-phenethyl isothiocyanate (PEITC), and sulforaphane in human breast cancer MCF-7 and human mammary epithelium MCF-12A cell lines, as well as in a second human epithelial cell line, human kidney HK-2 cells. The cytotoxicity

ELAINE TSENG; ELIZABETH A. SCOTT-RAMSAY; MARILYN E. MORRIS

2004-01-01

362

Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer  

Microsoft Academic Search

Amplification of the human epidermal growth factor receptor 2 protein (HER2) in primary breast carcinomas has been shown to correlate with poor clinical prognosis for certain patients. Trastuzumab (Herceptin®, Genentech, Inc., South San Francisco, California) is a highly purified recombinant DNA-derived humanized monoclonal immunoglobulin G1 kappa antibody that binds with high affinity and specificity to the extracellular domain of the

Marvin M. Goldenberg

1999-01-01

363

si-RNA-Mediated Silencing of ADRBK1 Gene Attenuates Breast Cancer Cell Proliferation.  

PubMed

Abstract Breast cancer is the most prominent cause of cancer-related deaths among women worldwide. It has been found that genetic mutations play distinct roles in the onset and progression of breast cancer. Androgenic, beta, receptor kinase 1 (ADRBK1) has been reported to possess oncogenic characteristics vital for cancer cell viability. This study was designed to investigate the effects of small interference RNA (si-RNA)-mediated ADRBK1 knockdown on breast cancer cell growth in vitro. High-expression levels of ADRBK1 were observed in all tested breast cancer cell lines (MDA-MB-231, MCF-7, T-47D, and BT-474). ADRBK1 si-RNA was delivered to breast cancer cells using lentivirus delivery system. Depletion of ADRBK1 significantly attenuated the cell viability and colony-formation ability. Flow cytometry analysis further demonstrated that ADRBK1 silencing led to MDA-MB-231 cell arrest in the G0/G1 phase. Collectively, these results indicate that knockdown of ADRBK1 gene has detrimental effects on breast cancer cell growth, which may be a potential therapeutic approach for the treatment of breast cancer. PMID:25279970

Zhang, Chen; Chen, Xianzhen; Li, Yongxin; S W A, Himaya; Wu, Jie; Shi, Xiujuan; Liu, Xiaoqing; Kim, Sekwon

2014-10-01

364

Activation of STAT3 is involved in malignancy mediated by CXCL12-CXCR4 signaling in human breast cancer.  

PubMed

The chemokine receptor CXCR4 and signal transducer and activator of transcription 3 (STAT3) play an important role in breast cancer malignancy and metastasis. However, it remains unknown whether STAT3 can be activated by CXCR4 in human breast cancer. The expression levels of CXCR4, STAT3 and p-STAT3 in 208 breast cancer tissues and 26 tumor-adjacent tissues were examined by immunohistochemistry. Flow cytometry, western blot analysis and immunoprecipitation were used to study activation of STAT3 by CXCL12-CXCR4 signaling in human breast cancer cell lines. The expression levels of CXCR4, STAT3 and p-STAT3 were higher in the breast cancer samples than these levels in the tumor-adjacent samples. The combined expression of CXCR4 and p-STAT3 was correlated with TNM stage, tumor size, lymph node metastasis and histological grade of breast cancer. In the breast cancer cells, CXCL12 treatment increased the expression of p-STAT3. The CXCR4 antagonist AMD3100 and the Janus kinase 2 (JAK2) antagonist AG490 inhibited the CXCL12-induced increase in the phosphorylation of STAT3. Furthermore, CXCL12 promoted direct binding of JAK2 to CXCR4. Our findings suggest that activation of the JAK2/STAT3 pathway via CXCL12-CXCR4 signaling plays an important role in breast cancer malignancy and metastasis. Targeting the CXCL12-CXCR4/JAK2/STAT3 signaling pathway may be a potential therapeutic strategy for the treatment of breast cancer. PMID:25310198

Liu, Xiaojian; Xiao, Qinghuan; Bai, Xuefeng; Yu, Zhaojin; Sun, Mingli; Zhao, Haishan; Mi, Xiaoyi; Wang, Enhua; Yao, Weifan; Jin, Feng; Zhao, Lin; Ren, Jie; Wei, Minjie