Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Not all breast cancers respond to tamoxifen, and many develop resistance despite initial benefit. We used an in vivo model of estrogen receptor (ER)-positive breast cancer (MCF-7 xenografts) to investigate mechanisms of this resistance and develop strategies to circumvent it. Epidermal growth factor receptor (EGFR) and HER2, which were barely detected in control estrogen-treated tumors, increased slightly with tamoxifen and were markedly increased when tumors became resistant. Gefitinib, which inhibits EGFR/HER2, improved the antitumor effect of tamoxifen and delayed acquired resistance, but had no effect on estrogen-stimulated growth. Phosphorylated levels of p42/44 and p38 mitogen-activated protein kinases (both downstream of EGFR/HER2) were increased in the tamoxifen-resistant tumors and were suppressed by gefitinib. There was no apparent increase in phosphorylated AKT (also downstream of EGFR/HER2) in resistant tumors, but it was nonetheless suppressed by gefitinib. Phosphorylated insulin-like growth factor-IR (IGF-IR), which can interact with both EGFR and membrane ER, was elevated in the tamoxifen-resistant tumors compared with the sensitive group. However, ER-regulated gene products, including total IGF-IR itself and progesterone receptor, remained suppressed even at the time of acquired resistance. Tamoxifen's antagonism of classic ER genomic function was retained in these resistant tumors and even in tumors that overexpress HER2 (MCF-7 HER2/18) and are de novo tamoxifen-resistant. In conclusion, EGFR/HER2 may mediate tamoxifen resistance in ER-positive breast cancer despite continued suppression of ER genomic function by tamoxifen. IGF-IR expression remains dependent on ER but is activated in the tamoxifen-resistant tumors. This study provides a rationale to combine HER inhibitors with tamoxifen in clinical studies, even in tumors that do not initially overexpress EGFR/HER2.
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PMID:Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. 1824 84

Cytokines and growth factors are responsible for inducing the expression of suppressor of cytokine signaling (SOCS) and cytokine-inducible SH2 containing (CIS) proteins. SOCS and CIS proteins are negative regulators of the JAK/STAT pathway, and exert their physiological effects by suppressing the tyrosine kinase activity of cytokine receptors and inhibiting STAT activation. Growth hormone (GH) is considered as a true cytokine and its local production directly contributes to tumor progression. In an initial study, we have found that CIS expression is increased in human breast cancer in proliferative areas corresponding to high level of GH synthesis. The results of the study presented here confirm the presence of a negative feed back loop in MCF7 cells stably transfected with the hGH gene (MCF-hGH). Real-time PCR analysis showed that gene expression levels of CIS were increased by 80% in MCF-hGH cells as compared to control cell line. Similarly, we have found that the level of CIS gene expression is increased by 50% in primary cultures of human breast cancer, reinforcing the pathophysiological impact of CIS. We previously demonstrated that increasing levels of transfected CIS resulted in strong activation of the mitogen-activated protein (MAP) kinase pathway. Thus, CIS protein has been hypothesized as acting like an activator of the MAPK pathway and an inhibitor of the differentiated cells functions mediated through the JAK/STAT pathway. In the present study, we demonstrate the role of CIS protein in tumor progression in particular its positive effects on cell proliferation and colony formation.
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PMID:Involvement of a JAK/STAT pathway inhibitor: cytokine inducible SH2 containing protein in breast cancer. 1849 55

The spatial organization of K-Ras proteins into nanoclusters on the plasma membrane is essential for high-fidelity signal transduction. The mechanism underlying K-Ras nanoclustering is unknown. We show here that K-Ras.GTP recruits Galectin-3 (Gal-3) from the cytosol to the plasma membrane where it becomes an integral nanocluster component. Importantly, we show that the cytosolic level of Gal-3 determines the magnitude of K-Ras.GTP nanoclustering and signal output. The beta-sheet layers of the Gal-3 carbohydrate recognition domain contain a hydrophobic pocket that may accommodate the farnesyl group of K-Ras. V125A substitution within this hydrophobic pocket yields a dominant negative Gal-3(V125A) mutant that inhibits K-Ras activity. Gal-3(V125A) interaction with K-Ras.GTP reduces K-Ras.GTP nanocluster formation, which abrogates signal output from the Raf/mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) pathway. Gal-3(V125A) negatively regulates cell growth and reduces cellular transformation. Thus, regulation of K-Ras nanocluster formation and signal output by Gal-3 critically depends on the integrity of the Gal-3 hydrophobic pocket. These results show that Gal-3 overexpression in breast cancer cells, which increases K-Ras signal output, represents oncogenic subversion of plasma membrane nanostructure.
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PMID:K-ras nanoclustering is subverted by overexpression of the scaffold protein galectin-3. 1870 84

Breast cancer development and breast cancer progression involves the deregulation of growth factors leading to uncontrolled cellular proliferation, invasion and metastasis. Transforming growth factor (TGF)-beta plays a crucial role in breast cancer because it has the potential to act as either a tumor suppressor or a pro-oncogenic chemokine. A cross-communication between the TGF-beta signaling network and estrogens has been postulated, which is important for breast tumorigenesis. Here, we provide evidence that inhibition of TGF-beta signaling is associated with a rapid estrogen-dependent nongenomic action. Moreover, we were able to demonstrate that estrogens disrupt the TGF-beta signaling network as well as TGF-beta functions in breast cancer cells via the G protein-coupled receptor 30 (GPR30). Silencing of GPR30 in MCF-7 cells completely reduced the ability of 17-beta-estradiol (E2) to inhibit the TGF-beta pathway. Likewise, in GPR30-deficient MDA-MB-231 breast cancer cells, E2 achieved the ability to suppress TGF-beta signaling only after transfection with GPR30-encoding plasmids. It is most interesting that the antiestrogen fulvestrant (ICI 182,780), which possesses agonistic activity at the GPR30, also diminished TGF-beta signaling. Further experiments attempted to characterize the molecular mechanism by which activated GPR30 inhibits the TGF-beta pathway. Our results indicate that GPR30 induces the stimulation of the mitogen-activated protein kinases (MAPKs), which interferes with the activation of Smad proteins. Inhibition of MAPK activity prevented the ability of E2 from suppressing TGF-beta signaling. These findings are of great clinical relevance, because down-regulation of TGF-beta signaling is associated with the development of breast cancer resistance in response to antiestrogens.
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PMID:17-Beta-estradiol inhibits transforming growth factor-beta signaling and function in breast cancer cells via activation of extracellular signal-regulated kinase through the G protein-coupled receptor 30. 1876 37

Three prominent hallmarks of triple-negative/basal-like breast carcinomas, a subtype of breast cancer gene phenotype associated with poor relapse-free and overall survival, are overexpression of the epidermal growth factor receptor (EGFR), hyperactivation of the MEK/ERK transduction pathway and high sensitivity to DNA-damaging agents. The cytotoxic interaction between EGFR inhibitors (monoclonal antibodies such as cetuximab and small molecule tyrosine kinase inhibitors such as gefitinib) and DNA cross-linking agents (e.g. platinum derivatives) might represent a promising combination for the treatment of triple-negative/basal-like breast tumors that are dependent upon EGFR/MEK/ERK signaling. We evaluated the growth and molecular interactions of the anti-EGFR antibody cetuximab (erbitux) and the DNA cross-linking agent cisplatin (cis-diammedichloroplatinum; CDDP) in the gefitinib-resistant MDA-MB-468 breast cancer cell line, an in vitro model system that shows many of the recurrent basal-like molecular abnormalities including ER-PR-HER2-negative status, TP53 deficiency, EGFR overexpression, PTEN loss and constitutive activation of the MEK/ERK pathway. Unlike other basal-like breast cancer models, MDA-MB-468 cells do not carry mutations of the key DNA repair gene BRCA1. Concurrent treatment with sub-optimal doses of cetuximab significantly enhanced CDDP-induced apoptotic cell death. However, an isobologram-based mathematical assessment of the nature of the interaction revealed a loss of synergism when employing a high-dose of cetuximab. Since BRCA1 depletion has been found to decrease DNA damage repair and cell survival in MDA-MB-468 cells when treated with DNA-damaging drugs, we employed ELISA-based quantitative analyses to measure BRCA1 protein levels in CDDP+/- cetuximab-treated cells. Cetuximab as single agent was as efficient as CDDP at increasing BRCA1 protein expression. Interestingly, cetuximab co-exposure significantly antagonized the ability of CDDP to up-regulate BRCA1 expression. Low-scale phosphor-proteomic approaches [i.e. phospho-receptor tyrosine kinase (RTK) and phospho-mitogen-activated protein kinases (MAPKs) Array Proteome Profiler capable of simultaneously identifying the relative levels of phosphorylation of 42 different RTKs and 23 different MAPKs and other serine/threonine kinases, respectively] revealed the ability of Cetuximab, as single agent, to paradoxically induce hyper-phosphorylation of EGFR while concomitantly deactivating p42/44 (ERK1/ERK2) MAPK. Unexpectedly, ELISA-based quantitative analyses of EGFR protein content demonstrated that simultaneous exposure to cetuximab and optimal doses of CDDP completely depleted EGFR protein in MDA-MB-468 cells. Although these findings preclinically support, at least in part, ongoing clinical trials for 'triple-negative/basal-like' metastatic breast cancer patients who are receiving either cetuximab alone versus cetuximab plus carboplatin (http://www.clinicaltrials.gov/ct/show/NCT00232505), the unexpected ability of CDDP to promote a complete depletion of the cetuximab target EGFR further suggests that treatment schedules, cetuximab/CDDP doses and BRCA1 status should be carefully considered when combining anti-EGFR antibodies and platinum derivatives in triple-negative/basal-like breast carcinomas.
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PMID:Growth and molecular interactions of the anti-EGFR antibody cetuximab and the DNA cross-linking agent cisplatin in gefitinib-resistant MDA-MB-468 cells: new prospects in the treatment of triple-negative/basal-like breast cancer. 1902 Jul 49

Kinin peptides exert multiple biological effects by binding to two types of G protein-coupled receptors known as B(1) (B(1)R) and B(2) receptors. Expression of the B(1)R in human breast cancer was recently reported, but up to now the consequences of its stimulation are unknown. Our aims were (1) to investigate the capacity of B(1)R to trigger cell proliferation in breast cancer cells, (2) to explore some of the downstream events occurring after B(1)R stimulation that may be linked to cell proliferation, and (3) to determine whether human breast tumors express potentially active B(1)R assessed by the binding of a radiolabeled agonist. Breast cancer cells expressed both the mRNA and the immunoreactive protein of B(1)R that once stimulated triggered cell proliferation at nanomolar concentrations of the ligand. Inhibitor studies suggested that the proliferative effects depend on the activity of epidermal growth factor receptor and subsequent ERK1/2 mitogen-activated protein kinases phosphorylation. B(1)R binding sites, were detected in 3/4 fibroadenomas, in 4/4 ductal carcinomas in situ and in 11/13 invasive ductal carcinomas. The B(1)R-epidermal growth factor receptor crosstalk may be a key interaction that maintains tumor growth, and antagonism of B(1)R may be a valuable alternative for the treatment of breast cancer.
Breast Cancer Res Treat 2009 Dec
PMID:Stimulation of the bradykinin B(1) receptor induces the proliferation of estrogen-sensitive breast cancer cells and activates the ERK1/2 signaling pathway. 1918 15

The aim of this study was to determine whether the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway is involved in genistein- and equol-induced cell proliferation and estrogen receptor (ER) alpha transactivation. For MCF-7 human breast cells, low concentrations of genistein and equol enhanced proliferation and induced MCF-7 cells to enter the S-phase. Genistein- and equol-induced cell proliferation and S-phase entry were blocked by the ERalpha antagonists 4-hydroxytamoxifen and ICI 182,780 and by the mitogen-activated protein kinase 1/2 inhibitor U0126. These data indicated that ERalpha and mitogen-activated protein extracellular kinase/ERK signaling were required for the effects of genistein/equol on cell growth and cell cycle progression. Genistein and equol induced delayed and prolonged activation of ERK1/2. Inhibition of ERK1/2 phosphorylation by U0126 led to complete suppression of genistein- and equol-induced estrogen response element reporter activity and to suppression of the estrogen-responsive gene pS2. The anti-estrogen ICI had no effect on genistein- and equol-induced ERK1/2 phosphorylation. These results suggest that activation of ERK1/2 lies upstream of ER-mediated transcription, and that ERK1/2 activation is necessary for the transactivation of ERalpha. In conclusion, genistein and equol elicit a delayed activation of ERK1/2, and this activation appears to be involved in the proliferation of breast cancer cells and estrogen-dependent transcriptional activation.
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PMID:Delayed activation of extracellular-signal-regulated kinase 1/2 is involved in genistein- and equol-induced cell proliferation and estrogen-receptor-alpha-mediated transcription in MCF-7 breast cancer cells. 1942 79

Progesterone receptors (PR) select and control genetic programs in the breast during normal mammary gland development, and progestin-driven processes contribute to the initiation and/or progression of breast cancer [Beral, V., 2003. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362, 419-427; Chlebowski, R.T., Hendrix, S.L., Langer, R.D., Stefanick, M.L., Gass, M., Lane, D., Rodabough, R.J., Gilligan, M.A., Cyr, M.G., Thomson, C.A., et al., 2003. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289, 3243-3253]. Throughout the mammalian life span, progesterone exerts varying biological consequences on the mammary epithelial compartment, from brief proliferative spurts that occur with each luteal phase of the menstrual cycle to the massive expansion of the pregnant gland in preparation for lactation [Brisken, C., Park, S., Vass, T., Lydon, J.P., O'Malley, B.W., Weinberg, R.A., 1998. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc. Natl. Acad. Sci. U.S.A. 95, 5076-5081; Ismail, P.M., Amato, P., Soyal, S.M., DeMayo, F.J., Conneely, O.M., O'Malley, B.W., Lydon, J.P., 2003. Progesterone involvement in breast development and tumorigenesis-as revealed by progesterone receptor "knockout" and "knockin" mouse models. Steroids 68, 779-787]. These processes, while important developmentally, can become deregulated in breast cancer, thereby contributing to unchecked proliferation, increased survival, and invasive behaviors. Recently, our lab has focused on the molecular mechanisms, including phosphorylation events, by which PRs select specific target genes in response to progestins and other mitogenic hormonal signals (i.e. EGF, heregulin). Herein, we discuss the actions of cytoplasmic signaling molecules such as c-Src and mitogen-activated protein kinases as key mediators of PR promoter selectivity.
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PMID:Signaling inputs to progesterone receptor gene regulation and promoter selectivity. 1954 91

Recently, we could show that gonadotropin-releasing hormone (GnRH)-II antagonists induce apoptosis in human endometrial, ovarian, and breast cancer cells in vitro and in vivo. In the present study, we have ascertained receptor binding and effects of GnRH-II antagonists on mitogenic signal transduction and on activation of proapoptotic protein Bax. The GnRH-II antagonists tested showed EC50 values for GnRH-I receptor binding in the range of 1 to 2 nmol/L. The GnRH-II agonist [D-Lys6]GnRH-II showed an EC50 value for GnRH-I receptor binding of approximately 1,000 nmol/L. Agonistic activity on GnRH-I receptor function with an EC50 of 13 nmol/L has been determined for [D-Lys6]GnRH-II. Antagonistic activities with EC50 values in the range of 1 nmol/L were determined for the GnRH-II antagonists. Treatment of human endometrial, ovarian, and breast cancer cells with GnRH-II antagonists resulted in time-dependent activation of stress-induced mitogen-activated protein kinases p38 and c-Jun NH2-terminal kinase. In addition, treatment with GnRH-II antagonists induced time-dependent activation of proapoptotic protein Bax. GnRH-II antagonists are not involved in activation of protein kinase B/Akt or extracellular signal-regulated kinase 1/2. The GnRH-II antagonists tested had similar binding affinities to the GnRH-I receptor comparable with that of GnRH-I antagonist Cetrorelix. Referring to the cyclic AMP response element reporter gene activation assay, the GnRH-II agonist [D-Lys6]GnRH-II has to be classified as an agonist at the GnRH-I receptor, whereas the GnRH-II antagonists tested are clear antagonists at the GnRH-I receptor. GnRH-II antagonists induce apoptotic cell death in human endometrial, ovarian, and breast cancer cells via activation of stress-induced mitogen-activated protein kinases p38 and c-Jun NH2-terminal kinase followed by activation of proapoptotic protein Bax.
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PMID:GnRH-II antagonists induce apoptosis in human endometrial, ovarian, and breast cancer cells via activation of stress-induced MAPKs p38 and JNK and proapoptotic protein Bax. 1963 91

The topical application of TPA (12-O-tetradecanoylphorbol-13-acetate) to animal skin or direct treatment of TPA to cell cultures leads to inflammatory responses by enhancing cyclooxygenase 2 (COX-2) expression, and specific COX-2 inhibitors counteract this kind of inflammatory response. Furthermore, suppression of these inflammatory events by dietary-origin chemopreventive agents can provide a potential strategy to control carcinogenesis. In this in vivo study, the mammary glands of mature female rats were treated with TPA, and then the effects of genistein alone or in combination with capsaicin on suppression of inflammatory responses were examined. The combined effects of genistein and capsaicin on COX-2, pJNK, pERK, and pp38 expressions were additive or nonadditive, depending on signals tested. In vitro MCF-7 breast cancer cells, the apoptotic bodies as shown with Hoechst 33342 dye, exhibited a synergistic effect between genistein and capsaicin. The abilities of genistein alone or in combination with capsaicin in inhibiting breast cancer cell proliferation through the modulation of AMPK and COX-2 were tested. AMPK activation by genistein in combination with capsaicin is critical for inhibiting COX-2. We propose that genistein in combination with capsaicin exerts anti-inflammatory and anticarcinogenic properties through the modulation of AMPK and COX-2 and possibly various mitogen-activated protein kinases synergistically or nonsynergistically.
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PMID:Anti-inflammatory and anticarcinogenic effect of genistein alone or in combination with capsaicin in TPA-treated rat mammary glands or mammary cancer cell line. 1972 84


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