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

Estrogen receptors alpha and beta (ERalpha and ERbeta) mediate the actions of estrogens in a variety of normal and cancer target cells. Estrogens differ in their preference for these ERs, and many phytoestrogens bind preferentially to ERbeta. To investigate how phytoestrogens such as genistein impact ER-regulated gene expression, we used adenoviral gene delivery of ERbeta coupled with ERalpha depletion with small interfering RNA to generate human breast cancer (MCF-7) cells expressing four complements of ERalpha and ERbeta. We examined the dose-dependent effects of genistein on genome-wide gene expression by DNA microarrays and monitored the recruitment of ERs and coregulators to responsive regions of estrogen-regulated genes. At a low (6 nm) concentration, genistein regulated gene expression much more effectively in cells coexpressing ERalpha and ERbeta than in cells expressing ERalpha alone, whereas at high concentration (300 nm), genistein induced transcriptome changes very similar to that of 17beta-estradiol. We demonstrate that ERbeta is preferentially activated by genistein and is recruited to estrogen-responsive genomic sites and that differential occupancy of ERalpha and ERbeta by genistein and 17beta-estradiol in turn influences the recruitment patterns of coregulators such as steroid receptor coactivator 3 (SRC3) and receptor-interacting protein 140 (RIP140). Our observations indicate that genistein is a potency-selective ligand for gene expression regulation by ERalpha and ERbeta and that the ability of ERalpha and ERbeta to serve as determinants of gene expression is greatly influenced by the nature of the ligand, by ligand dose, and by the differential abilities of ligand-ER complexes to recruit different coregulators at ER binding sites of hormone-regulated genes.
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PMID:Estrogen Receptors alpha and beta as determinants of gene expression: influence of ligand, dose, and chromatin binding. 1825 89

Overexpression of the oncogene amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) induces mammary tumorigenesis in mice. In breast cancer, high levels of AIB1/SRC-3 and the growth factor receptor HER2/neu predict resistance to endocrine therapy and poor outcome. However, a mechanistic relationship between AIB1/SRC-3 and HER2/neu in the development of breast cancer has not been shown. Here, we show that deletion of one allele of SRC-3 significantly delays Neu-induced mammary tumor development in mice. Homozygous deletion of SRC-3 in mice completely prevents Neu-induced tumor formation. By ages 3 to 4 months, Neu/SRC-3(+/-) mice exhibit a noticeable reduction in lateral side-bud formation, accompanied by reduced cellular levels of phosphorylated Neu compared with Neu/SRC-3(wt) mice. In Neu-induced tumors, high levels of SRC-3, phosphorylated Neu, cyclin D1, cyclin E, and proliferating cell nuclear antigen expression are observed, accompanied by activation of the AKT and c-Jun NH(2) kinase (JNK) signaling pathways. In comparison, phosphorylated Neu, cyclin D1, and cyclin E are significantly decreased in Neu/SRC-3(+/-) tumors, proliferation is reduced, and AKT and JNK activation is barely detectable. Our data indicate that AIB1/SRC-3 is required for HER2/neu oncogenic activity and for the phosphorylation and activation of the HER2/neu receptor. We predict that reducing AIB1/SRC-3 levels or activity in the mammary epithelium could potentiate therapies aimed at inhibiting HER2/neu signaling in breast cancer.
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PMID:The nuclear receptor coactivator amplified in breast cancer-1 is required for Neu (ErbB2/HER2) activation, signaling, and mammary tumorigenesis in mice. 1848 52

Overexpression of steroid receptor coactivator 3 (SRC-3) is associated with an increased incidence of breast cancer. A recent study shows that SRC-3 is protected from proteasomal degradation by atypical protein kinase C (aPKC)-mediated phosphorylation in an estrogen receptor alpha (ERalpha)-dependent manner. This finding provides a novel mechanism for coupling increased SRC-3 expression with enhanced estrogen-dependent cellular proliferation.
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PMID:Atypical regulation of SRC-3. 1850 45

The importance of the progesterone receptor (PR) in transducing the progestin signal is firmly established in female reproductive and mammary gland biology; however, the coregulators preferentially recruited by PR in these systems have yet to be comprehensively investigated. Using an innovative genetic approach, which ablates gene function specifically in murine cell-lineages that express PR, steroid receptor coactivator 2 (SRC-2, also known as TIF-2 or GRIP-1) was shown to exert potent coregulator properties in progestin-dependent responses in the uterus and mammary gland. Uterine cells positive for PR (but devoid of SRC-2) led to an early block in embryo implantation, a phenotype not shared by knockouts for SRC-1 or SRC-3. In the case of the mammary gland, progestin-dependent branching morphogenesis and alveologenesis failed to occur in the absence of SRC-2, thereby establishing a critical coactivator role for SRC-2 in cellular proliferative programs initiated by progestins in this tissue. Importantly, the recent detection of SRC-2 in both human endometrium and breast suggests that this coregulator may provide a new clinical target for the future management of female reproductive health and/or breast cancer.
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PMID:Steroid receptor coactivator 2: an essential coregulator of progestin-induced uterine and mammary morphogenesis. 1854 May 68

Overexpression and activation of the steroid receptor coactivator amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) have been shown to have a critical role in oncogenesis and are required for both steroid and growth factor signaling in epithelial tumors. Here, we report a new mechanism for activation of SRC coactivators. We demonstrate regulated tyrosine phosphorylation of AIB1/SRC-3 at a C-terminal tyrosine residue (Y1357) that is phosphorylated after insulin-like growth factor 1, epidermal growth factor, or estrogen treatment of breast cancer cells. Phosphorylated Y1357 is increased in HER2/neu (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2) mammary tumor epithelia and is required to modulate AIB1/SRC-3 coactivation of estrogen receptor alpha (ERalpha), progesterone receptor B, NF-kappaB, and AP-1-dependent promoters. c-Abl (v-Abl Abelson murine leukemia viral oncogene homolog 1) tyrosine kinase directly phosphorylates AIB1/SRC-3 at Y1357 and modulates the association of AIB1 with c-Abl, ERalpha, the transcriptional cofactor p300, and the methyltransferase coactivator-associated arginine methyltransferase 1, CARM1. AIB1/SRC-3-dependent transcription and phenotypic changes, such as cell growth and focus formation, can be reversed by an Abl kinase inhibitor, imatinib. Thus, the phosphorylation state of Y1357 can function as a molecular on/off switch and facilitates the cross talk between hormone, growth factor, and intracellular kinase signaling pathways in cancer.
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PMID:Tyrosine phosphorylation of the nuclear receptor coactivator AIB1/SRC-3 is enhanced by Abl kinase and is required for its activity in cancer cells. 1876 37

As an alternative approach to blocking estrogen action, we have developed small molecules that directly disrupt the key estrogen receptor (ER)/coactivator interaction necessary for gene activation. The more direct, protein-protein nature of this disruption might be effective even in hormone-refractory breast cancer. We have synthesized a pyrimidine-core library of moderate size, members of which act as alpha-helix mimics to block the ERalpha/coactivator interaction. Structure-activity relationships have been explored with various C-, N-, O-, and S-substituents on the pyrimidine core. Time-resolved fluorescence resonance energy transfer and cell-based reporter gene assays show that the most active members inhibit the ERalpha/steroid receptor coactivator interaction with K i's in the low micromolar range. Through these studies, we have obtained a refined pharmacophore model for activity in this pyrimidine series. Furthermore, the favorable activities of several of these compounds support the feasibility that this coactivator binding inhibition mechanism for blocking estrogen action might provide a potential alternative approach to endocrine therapy.
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PMID:Blocking estrogen signaling after the hormone: pyrimidine-core inhibitors of estrogen receptor-coactivator binding. 1878 25

Cytochrome P450 (CYP) 1A1 and CYP1B1 are inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in the human breast cancer cell line, MCF-7. Since CYP1A1 was inducible to a much greater degree than CYP1B1, we hypothesized that there may be differences in coactivator recruitment to the promoter and/or enhancer regions of these genes. Dioxin treatment leads to recruitment of the aryl hydrocarbon receptor to the enhancer regions but not to the proximal promoter regions of both the CYP1A1 and CYP1B1 genes. On the other hand, dioxin treatment facilitated recruitment of RNA polymerase II to the promoters but not the enhancer regions. Dioxin treatment also elicited recruitment of the transcriptional coactivators, steroid receptor coactivator 1 (SRC-1) and steroid receptor coactivator 2 (SRC-2) and p300, which possess intrinsic histone acetyltranferase activities, to both genes, whereas Brahma (BRM)/Switch 2-related gene 1 (BRG-1), a subunit of nucleosomal remodeling factors, was recruited more robustly to CYP1A1 relative to CYP1B1. Small inhibitory RNA-mediated knockdown of p300 and SRC-2 adversely affected dioxin induction of both genes, whereas knockdown of BRM/BRG-1 reduced CYP1A1 induction but had little, if any, effect on CYP1B1 induction. These results suggest that nucleosomal remodeling is less significant for dioxin-mediated induction of CYP1B1 than that of CYP1A1 and may be related to the more modest inducibility of the former. Interestingly, simultaneous knockdown of SRC-2 and BRM/BRG-1 had no greater effect on CYP1A1 induction than knockdown of each coactivator individually, while simultaneous knockdown of p300 and BRM/BRG-1 had a much greater effect than knockdown of each individual gene, suggesting that the recruitment of SRC-2 to CYP1A1 depends upon BRM/BRG-1, while the recruitments of p300 and BRM/BRG-1 are independent of each other. These observations provide novel insights into the functional roles of the endogenous coactivators in dioxin induction of the human CYP1A1 and CYP1B1 genes in their natural chromosomal configurations.
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PMID:Roles of coactivator proteins in dioxin induction of CYP1A1 and CYP1B1 in human breast cancer cells. 1884 20

Each of the three members of the p160 steroid receptor coactivator (SRC) family of coactivators (SRC-1, SRC-2 and SRC-3) stimulates estrogen receptor (ER)-alpha function in trans-activation assays. Consequently, we sought to elucidate their contributions to the ER-regulated processes of cell proliferation, apoptosis, and the expression of ERalpha target genes in MCF-7 breast cancer cells. The small interfering RNA depletion of SRC-2 or SRC-3 but not SRC-1 inhibited growth of MCF-7 cells, and this was reflected in decreased cell cycle progression and increased apoptosis in SRC-2- or SRC-3-depleted cells as well as a reduction in ERalpha transcriptional activity measured on a synthetic reporter gene. However, only SRC-3 depletion blocked estradiol stimulated cell proliferation. Depletion of SRC-1 did not affect these events, and together this reveals functional differences between each of the three SRC family coactivators. Regulation of the endogenous ERalpha target gene, c-myc was not affected by depletion of any of the p160 coactivators although depletion of each of them decreased pS2 mRNA expression in estradiol-treated MCF-7 cells. Moreover, progesterone receptor and cyclin D1 gene expression were decreased in SRC-3 small interfering RNA-treated cells. Expression of mRNA and protein levels for the antiapoptotic gene, Bcl-2 was dependent on SRC-3 expression, whereas Bcl-2 protein but not mRNA expression also was sensitive to SRC-1 depletion. Together these data indicate that the closely related p160 coactivators are not functionally redundant in breast cancer cells because they play gene-specific roles in regulating mRNA and protein expression, and they therefore are likely to make unique contributions to breast tumorigenesis.
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PMID:Unique roles of p160 coactivators for regulation of breast cancer cell proliferation and estrogen receptor-alpha transcriptional activity. 1909 46

Therapeutic block of estrogen action is typically achieved with conventional antagonists (CAs), compounds that displace estradiol from the estrogen receptor (ER) and induce formation of an ER conformation that cannot bind to coactivator proteins, such as the steroid receptor coactivators (SRCs). As an alternative mode for blocking estrogen action, the authors seek small molecules that act as coactivator binding inhibitors (CBIs)-that is, they compete directly with SRC3 for interaction with estradiol-bound ER. CBIs would be interesting mechanistic probes of estrogen action and might also provide an alternative, more durable endocrine therapy for hormone-responsive breast cancer, where cellular adaptations lead to resistance to CAs. The authors have designed and optimized a set of time-resolved fluorescence resonance energy transfer (TR-FRET) assays to monitor the interaction of ER with SRC3 and ligands, and they have used them in high-throughput screens to discover small-molecule CBIs that are able to disrupt this interaction. These assays also distinguish CBIs from CAs. These robust and sensitive "mix-and-measure" assays use low concentrations of ER labeled with a europium chelate as FRET donor and a Cy5-labeled SRC as acceptor. This multiplexed protocol produces excellent signal-to-noise ratios (>100) and Z' values (>0.8).
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PMID:A set of time-resolved fluorescence resonance energy transfer assays for the discovery of inhibitors of estrogen receptor-coactivator binding. 1919 99

Epidermal growth factor (EGF) receptor (EGFR)/MAPK signaling can induce a switch in MCF-7 breast cancer cells, from an estrogen receptor (ER)alpha-positive, Luminal-A phenotype, to an ERalpha-negative, Basal-like phenotype. Although mechanisms for this switch remain obscure, Basal-like cancers are typically high grade and confer a poorer clinical prognosis. We previously reported that miR-206 and ERalpha repress each other's expression in MCF-7 cells in a double-negative feedback loop. We show herein that miR-206 coordinately targets mRNAs encoding the coactivator proteins steroid receptor coactivator (SRC)-1 and SRC-3, and the transcription factor GATA-3, all of which contribute to estrogenic signaling and a Luminal-A phenotype. Overexpression of miR-206 repressed estrogen-mediated responses in MCF-7 cells, even in the presence of ERalpha encoded by an mRNA lacking a 3'-untranslated region, suggesting miR-206 affects estrogen signaling by targeting mRNAs encoding ERalpha-associated coregulatory proteins. Furthermore, EGF treatments enhanced miR-206 levels in MCF-7 cells and ERalpha-negative, EGFR-positive MDA-MB-231 cells, whereas EGFR small interfering RNA, or PD153035, an EGFR inhibitor, or U0126, a MAPK kinase inhibitor, significantly reduced miR-206 levels in MDA-MB-231 cells. Blocking EGF-induced enhancement of miR-206 with antagomiR-206 abrogated the EGF-inhibitory effect on ERalpha, SRC-1, and SRC-3 levels, and on estrogen response element-luciferase activity, indicating that EGFR signaling represses estrogenic responses in MCF-7 cells by enhancing miR-206 activity. Elevated miR-206 levels in MCF-7 cells ultimately resulted in reduced cell proliferation, enhanced apoptosis, and reduced expression of multiple estrogen-responsive genes. In conclusion, miR-206 contributes to EGFR-mediated abrogation of estrogenic responses in MCF-7 cells, contributes to a Luminal-A- to Basal-like phenotypic switch, and may be a measure of EGFR response within Basal-like breast tumors.
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PMID:The role of miR-206 in the epidermal growth factor (EGF) induced repression of estrogen receptor-alpha (ERalpha) signaling and a luminal phenotype in MCF-7 breast cancer cells. 1942 51


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