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Cooperative interaction between retinoic acid receptor-alpha and estrogen receptor in breast cancer.

ABSTRACT: Retinoic acid receptor-alpha (RAR alpha) is a known estrogen target gene in breast cancer cells. The consequence of RAR alpha induction by estrogen was previously unknown. We now show that RAR alpha is required for efficient estrogen receptor-alpha (ER)-mediated transcription and cell proliferation. RAR alpha can interact with ER-binding sites, but this occurs in an ER-dependent manner, providing a novel role for RAR alpha that is independent of its classic role. We show, on a genome-wide scale, that RAR alpha and ER can co-occupy regulatory regions together within the chromatin. This transcriptionally active co-occupancy and dependency occurs when exposed to the predominant breast cancer hormone, estrogen--an interaction that is promoted by the estrogen-ER induction of RAR alpha. These findings implicate RAR alpha as an essential component of the ER complex, potentially by maintaining ER-cofactor interactions, and suggest that different nuclear receptors can cooperate for effective transcriptional activity in breast cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22213 | GEO | 2010/06/09

SECONDARY ACCESSION(S): PRJNA128765

REPOSITORIES: GEO

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Cooperative interaction between retinoic acid receptor-alpha and estrogen receptor in breast cancer.

Project description:Retinoic acid receptor-alpha (RAR alpha) is a known estrogen target gene in breast cancer cells. The consequence of RAR alpha induction by estrogen was previously unknown. We now show that RAR alpha is required for efficient estrogen receptor-alpha (ER)-mediated transcription and cell proliferation. RAR alpha can interact with ER-binding sites, but this occurs in an ER-dependent manner, providing a novel role for RAR alpha that is independent of its classic role. We show, on a genome-wide scale, that RAR alpha and ER can co-occupy regulatory regions together within the chromatin. This transcriptionally active co-occupancy and dependency occurs when exposed to the predominant breast cancer hormone, estrogen--an interaction that is promoted by the estrogen-ER induction of RAR alpha. These findings implicate RAR alpha as an essential component of the ER complex, potentially by maintaining ER-cofactor interactions, and suggest that different nuclear receptors can cooperate for effective transcriptional activity in breast cancer cells. RAR alpha silenced breast cancer MCF-7 cell lines or control siRNA in the presence of estrogen or a vehicle. MCF-7 cells were hormone-depleted for 3 d and treated with 100 nM estrogen for 12 h. There were three biological replicates for each of the four different groups.

2010-06-16 | E-GEOD-22213 | biostudies-arrayexpress

Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes

Project description:Progesterone and estrogen are important drivers of breast cancer proliferation. Herein, we probed estrogen receptor-α (ER) and progesterone receptor (PR) cross-talk in breast cancer models. Stable expression of PR-B in PR-low/ER+ MCF7 cells increased cellular sensitivity to estradiol and insulin-like growth factor 1 (IGF1), as measured in growth assays performed in the absence of exogenous progestin; similar results were obtained in PR-null/ER+ T47D cells stably expressing PR-B. Genome-wide microarray analyses revealed that unliganded PR-B induced robust expression of a subset of estradiol-responsive ER target genes, including cathepsin-D (CTSD). Estradiol-treated MCF7 cells stably expressing PR-B exhibited enhanced ER Ser167 phosphorylation and recruitment of ER, PR and the proline-, glutamate- and leucine-rich protein 1 (PELP1) to an estrogen response element in the CTSD distal promoter; this complex co-immunoprecipitated with IGF1 receptor (IGFR1) in whole-cell lysates. Importantly, ER/PR/PELP1 complexes were also detected in human breast cancer samples. Inhibition of IGF1R or phosphoinositide 3-kinase blocked PR-B-dependent CTSD mRNA upregulation in response to estradiol. Similarly, inhibition of IGF1R or PR significantly reduced ER recruitment to the CTSD promoter. Stable knockdown of endogenous PR or onapristone treatment of multiple unmodified breast cancer cell lines blocked estradiol-mediated CTSD induction, inhibited growth in soft agar and partially restored tamoxifen sensitivity of resistant cells. Further, combination treatment of breast cancer cells with both onapristone and IGF1R tyrosine kinase inhibitor AEW541 was more effective than either agent alone. In summary, unliganded PR-B enhanced proliferative responses to estradiol and IGF1 via scaffolding of ER-α/PELP1/IGF1R-containing complexes. Our data provide a strong rationale for targeting PR in combination with ER and IGF1R in patients with luminal breast cancer.

2015-03-15 | GSE45643 | GEO

Neurofibromin is an Estrogen Receptor alpha Transcriptional Co-repressor in Breast cancer

Project description:We report that neurofibromin, a tumor suppressor and Ras-GAP (GTPase Activating Protein), is also an estrogen receptor-alpha (ER) transcriptional co-repressor through leucine/isoleucine-rich motifs that are functionally independent of GAP activity. GAP activity, in turn, does not impact ER binding. Consequently, neurofibromin-depletion causes estradiol hypersensitivity and tamoxifen agonism, explaining the poor prognosis associated with neurofibromin-loss in endocrine therapy-treated ER+ breast cancer. Neurofibromin-deficient ER+ breast cancer cells initially retain sensitivity to selective estrogen receptor degraders (SERDs). However, Ras activation does play a role in acquired SERD resistance, which can be reversed upon MEK inhibitor addition, and SERD/MEK inhibitor combinations induce tumor regression. Thus, neurofibromin is a dual repressor for both Ras and ER signaling, and co-targeting may treat neurofibromin-deficient ER+ breast tumors.

2020-02-14 | GSE142479 | GEO

Cancer-associated fibroblasts rewire the estrogen receptor response in luminal breast cancer, enabling estrogen independence

Project description:Advanced breast cancers represent a major therapeutic challenge due to their refractoriness to treatment. Cancer-associated fibroblasts (CAFs) are the most abundant constituents of the tumor microenvironment and have been linked to most hallmarks of cancer. However, the influence of CAFs on therapeutic outcome remains largely unchartered. Here, we reveal that spatial coincidence of abundant CAF infiltration with malignant cells was associated with reduced estrogen receptor (ER)-α expression in luminal breast tumors. Notably, CAFs mediated estrogen-independent tumor growth by selectively regulating ER-α signaling. Whereas most prototypical estrogen-responsive genes were suppressed, CAFs maintained gene expression related to therapeutic resistance. A high-throughput drug screen in co-cultures identified effector pathways involved in the CAF-induced regulation of ER-α signaling. Among these, the transforming growth factor-β and the janus kinase signaling cascades were validated as actionable targets to counteract the CAF-induced ER-α modulation. Finally, genes that were downregulated in cancer cells by CAFs were predictive of poor response to endocrine treatment. In conclusion, our work reveals that CAFs directly control the luminal breast cancer phenotype by selectively modulating ER-α expression and transcriptional function, and further proposes novel targets to disrupt the crosstalk between CAFs and tumor cells to reinstate treatment response to endocrine therapy in patients.

2024-02-23 | GSE251644 | GEO

Genome-wide Binding Site Mapping of Estrogen Receptor alpha and c-MYC in Breast Cancer Cells

Project description:Estrogens are steroid hormones that play critical roles in the initiation, development, and metastasis of breast and uterine cancers. The estrogen (E2) response in breast cancer cells is predominantly mediated by the estrogen receptor-alpha (ER alpha), a ligand-activated transcription factor. ER alpha regulates transcription of target genes through direct binding to its cognate recognition sites, known as estrogen response elements (EREs), or by modulating the activity of other DNA-bound transcription factors at alternative DNA sequences. The proto-oncogene c-myc is upregulated by ERÂ¦Ã in response to E2 and encodes a transcription factor, c-MYC, which regulates a cascade of gene targets whose products mediate cellular transformation. This study aims at mapping the binding sites of these two transcription factors (ER alpha and c-MYC) in one ER alpha positive breast cancer cell line (MCF7 cell line). Keywords: ChIP-Chip Analysis This series contains ChIP-on-Chip data sets for two transcription factors (ER alpha and c-MYC) and control samples (INPUT). All the experiments are done in triplicates. MCF7 Cells were E2-deprived for 3 days and then were treated with 10 nM E2 (45 minutes and 2 hours for mapping ER alpha and c-MYC binding sites, respectively) at 80% confluence.

2010-05-26 | E-GEOD-10800 | biostudies-arrayexpress

Transcription profiling of mouse model of estrogen receptor positive breast cancer lymph node metastasis.

Project description:The lymphatic system is a common avenue for the spread of breast cancer cells and dissemination through it occurs at least as frequently as hematogenous metastasis. Approximately 75% of primary breast cancers are estrogen receptor (ER) positive and the majority of these maintain receptor expression as lymph node (LN) metastases. However, it is unknown if ER function is equivalent in cancer cells growing in the breast and in the LNs. We have developed a model to assess estrogen responsiveness in ER(+) breast tumors and LN metastases. Fluorescent ER(+) MCF-7 tumors were grown in ovariectomized nude mice supplemented with estradiol. Once axillary LN metastasis arose, estradiol was withdrawn (EWD), for 1 or 4 weeks, or continued, to assess estradiol responsiveness. On EWD, proliferation rates fell similarly in tumors and LN metastases. However, estradiol-dependent ER down-regulation and progesterone receptor induction were deficient in LN metastases, indicating that ER-dependent transcriptional function was altered in the LN. Cancer cells from estradiol-treated and EWD primary tumors and matched LN metastases were isolated by laser capture microdissection. Global gene expression profiling identified transcripts that were regulated by the tissue microenvironment, by hormones, or by both. Interestingly, numerous genes that were estradiol regulated in tumors lost estradiol sensitivity or were regulated in the opposite direction by estradiol in LN metastases. We propose that the LN microenvironment alters estradiol signaling and may contribute to local antiestrogen resistance. Experiment Overall Design: 10 samples, including 3 each of estrogen and estrogen withdrawn axillary lymph nodes and 2 each of estrogen and estrogen withdrawn primary mammary gland tumors.

2008-06-11 | E-GEOD-11317 | biostudies-arrayexpress

FoxA1 is a critical determinant of Estrogen Receptor function and endocrine response (part I)

Project description:Estrogen Receptor-a (ER) is the key feature in the majority of breast cancers and ER binding to the genome correlates with the Forkhead protein FOXA1 (HNF3a), but mechanistic insight is lacking. We now show that FOXA1 is the defining factor that governs differential ER-chromatin interactions. We show that almost all ER-chromatin interactions and gene expression changes are dependent on the presence of FOXA1 and that FOXA1 dictates genome-wide chromatin accessibility. Furthermore, we show that CTCF is an upstream negative regulator of FOXA1-chromatin interactions. In ER responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity is absolute and in tamoxifen resistant cells, ER binding occurs independently of ligand, but in a FOXA1 dependent manner. Importantly, expression of FOXA1 in non-breast cancer cells is sufficient to alter ER binding and response to endocrine treatment. As such, FOXA1 is the primary determinant that regulates estrogen-ER activity and endocrine response in breast cancer cells and is sufficient to program ER functionality in non-breast cancer contexts. breast cancer MCF-7 cell lines were treaated in the presence of Estrogen, Estrogen plus Tamoxifen, Tamoxifen or a vehicle. MCF-7 cells were hormone-depleted for 3 d and treated with 100 nM estrogen or 1 microM Tamoxifen for 6 h. There were four biological replicates for each of the four different groups.

2010-11-17 | E-GEOD-25314 | biostudies-arrayexpress

Genome-wide Binding Site Mapping of Estrogen Receptor alpha and c-MYC in Breast Cancer Cells

Project description:Estrogens are steroid hormones that play critical roles in the initiation, development, and metastasis of breast and uterine cancers. The estrogen (E2) response in breast cancer cells is predominantly mediated by the estrogen receptor-alpha (ER alpha), a ligand-activated transcription factor. ER alpha regulates transcription of target genes through direct binding to its cognate recognition sites, known as estrogen response elements (EREs), or by modulating the activity of other DNA-bound transcription factors at alternative DNA sequences. The proto-oncogene c-myc is upregulated by ER¦Á in response to E2 and encodes a transcription factor, c-MYC, which regulates a cascade of gene targets whose products mediate cellular transformation. This study aims at mapping the binding sites of these two transcription factors (ER alpha and c-MYC) in one ER alpha positive breast cancer cell line (MCF7 cell line). Keywords: ChIP-Chip Analysis

2008-03-13 | GSE10800 | GEO

RNA sequencing to identify fusion transcripts in late-stage relapse patients with estrogen receptor positive breast cancer

Project description:RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor positive (ER+) breast cancer but their role in disease pathogenesis remains unclear. We performed sequencing on RNA extracted from metastatic biopsy samples from patients with ER+ breast cancer to assess the presence of fusion transcripts.

2021-11-23 | GSE189389 | GEO

FoxA1 is a critical determinant of Estrogen Receptor function and endocrine response (part II)

Project description:Estrogen Receptor-a (ER) is the key feature in the majority of breast cancers and ER binding to the genome correlates with the Forkhead protein FOXA1 (HNF3a), but mechanistic insight is lacking. We now show that FOXA1 is the defining factor that governs differential ER-chromatin interactions. We show that almost all ER-chromatin interactions and gene expression changes are dependent on the presence of FOXA1 and that FOXA1 dictates genome-wide chromatin accessibility. Furthermore, we show that CTCF is an upstream negative regulator of FOXA1-chromatin interactions. In ER responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity is absolute and in tamoxifen resistant cells, ER binding occurs independently of ligand, but in a FOXA1 dependent manner. Importantly, expression of FOXA1 in non-breast cancer cells is sufficient to alter ER binding and response to endocrine treatment. As such, FOXA1 is the primary determinant that regulates estrogen-ER activity and endocrine response in breast cancer cells and is sufficient to program ER functionality in non-breast cancer contexts. FoxA1 silenced breast cancer MCF-7 cell lines or control siRNA in the presence of Estrogen or a vehicle. MCF-7 cells were hormone-depleted for 3 d and treated with 100 nM estrogen for 6 h. There were three biological replicates for each of the four different groups.

2010-11-17 | E-GEOD-25315 | biostudies-arrayexpress

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