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Maintenance of Hormone Responsiveness in Luminal Breast Cancers by Suppression of Notch

ABSTRACT: Luminal breast cancers express estrogen (ER) and/or progesterone (PR) receptors and respond to hormone therapies. Basal-like “triple negative” (TN) cancers lack steroid receptors but are cytokeratin (CK) 5-positive and require chemotherapy. Here we show that over half of primary ER+PR+ breast cancers contain an ER–PR–CK5+ “luminobasal” subpopulation exceeding 1% of cells. Starting from ER+PR+ luminal cell lines, we generated novel lines with varying luminal to luminobasal-cell ratios and studied their molecular and biological properties. In luminal disease, luminobasal cells expand in response to antiestrogen or estrogen withdrawal therapies. The phenotype and gene signature of the hormone resistant cells matches that of clinical TN basal-like and claudin-low disease. Luminobasal-cell expansion in response to hormone therapies is regulated by Notch1 signaling and can be blocked by gamma-secretase inhibitors (GSI). Our data establish a previously unrecognized plasticity of ER+PR+ luminal breast cancers that, without genetic manipulation, mobilizes outgrowth of hormone-resistant basal-like disease in response to treatment. This undesirable outcome can be prevented by combining endocrine therapies with Notch inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE31870 | GEO | 2011/12/21

SECONDARY ACCESSION(S): PRJNA145071

REPOSITORIES: GEO

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Maintenance of Hormone Responsiveness in Luminal Breast Cancers by Suppression of Notch

Project description:Luminal breast cancers express estrogen (ER) and/or progesterone (PR) receptors and respond to hormone therapies. Basal-like “triple negative” (TN) cancers lack steroid receptors but are cytokeratin (CK) 5-positive and require chemotherapy. Here we show that over half of primary ER+PR+ breast cancers contain an ER–PR–CK5+ “luminobasal” subpopulation exceeding 1% of cells. Starting from ER+PR+ luminal cell lines, we generated novel lines with varying luminal to luminobasal-cell ratios and studied their molecular and biological properties. In luminal disease, luminobasal cells expand in response to antiestrogen or estrogen withdrawal therapies. The phenotype and gene signature of the hormone resistant cells matches that of clinical TN basal-like and claudin-low disease. Luminobasal-cell expansion in response to hormone therapies is regulated by Notch1 signaling and can be blocked by gamma-secretase inhibitors (GSI). Our data establish a previously unrecognized plasticity of ER+PR+ luminal breast cancers that, without genetic manipulation, mobilizes outgrowth of hormone-resistant basal-like disease in response to treatment. This undesirable outcome can be prevented by combining endocrine therapies with Notch inhibition. 24 array samples

2011-12-21 | E-GEOD-31870 | biostudies-arrayexpress

Modeling Luminal breast cancer heterogeneity: Combination therapy to suppress hormone receptor negative cells in Luminal disease

Project description:Many Luminal breast cancers are heterogeneous, containing substantial numbers of estrogen (ER-) and progesterone (PR-) receptor-negative cells among the ER+PR+ ones. Currently, the Basal-like ER-PR- Luminobasal subpopulation in Luminal disease is not targeted for treatment. To address the relationships between ER+PR+ and ER-PR- cells in Luminal cancers and tightly control their ratios, we have generated isogenic pure Luminal (pLUM) and pure Luminobasal (pLB) cells from the same parental Luminal human breast cancer cell line. We show that pLUM suppress proliferation of pLB cells in mixed-cell 3D colonies in vitro and in pLUM:pLB mixed-cell xenografts in mice. High-throughput screening of FDA-approved oncology drugs reveal pLB cells are sensitive to the EGFR inhibitors Gefitinib and Erlotinib. In mixed-cell 3D colonies and mixed-cell solid mouse tumors, combination therapy with the antiestrogen Fulvestrant and the EGFRi Gefitinib constitutes a robust treatment strategy. We propose that response to combination endocrine/EGFRi therapies in heterogeneous Luminal cancers will improve long-term survival in patients whose primary tumors have been preselected for the appropriate biomarkers.

2014-07-14 | GSE55350 | GEO

Genomic Regulation of Invasion by STAT3 in Triple Negative Breast Cancer

Project description:Breast cancer is a heterogeneous disease comprised of four molecular subtypes defined by whether the tumor-originating cells are luminal or basal epithelial cells. Breast cancers arising from the luminal mammary duct often express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2). Tumors expressing ER and/or PR are treated with anti-hormonal therapies, while tumors overexpressing HER2 are targeted with monoclonal antibodies. Immunohistochemical detection of ER, PR, and HER2 receptors/proteins is a critical step in breast cancer diagnosis and guided treatment. Breast tumors that do not express these proteins are known as “triple negative breast cancer” (TNBC) and are typically basal-like. TNBCs are the most aggressive subtype, with the highest mortality rates and no targeted therapy, so there is a pressing need to identify important TNBC tumor regulators. The signal transducer and activator of transcription 3 (STAT3) transcription factor has been previously implicated as a constitutively active oncogene in TNBC. However, its direct regulatory gene targets and tumorigenic properties have not been well characterized. By integrating RNA-seq and ChIP-seq data from 2 TNBC tumors and 4 cell lines, we discovered novel gene signatures directly regulated by STAT3 that were enriched for processes involving inflammation, immunity, and invasion in TNBC. Functional analysis revealed that STAT3 has a key role regulating invasion and metastasis, a characteristic often associated with TNBC. Our findings suggest therapies targeting STAT3 may be important for preventing TNBC metastasis.

2017-06-10 | GSE85579 | GEO

Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer. [ChIP-seq]

2016-06-01 | GSE80367 | GEO

Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer. [cell models RNA-seq]

2016-06-01 | GSE80366 | GEO

Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer. [tumor samples RNA-seq]

2016-06-01 | GSE80365 | GEO

Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer. [ChIP-seq]

Project description:Transcriptomic changes and estrogen and progesterone receptor binding in multiple ER+/PR+ models (eight ER+/PR+ patient tumors, various T47Ds, ZR75) and multiple ER+/PR-negative models (four ER+/PR- patient tuumors, PR-deficient T47D and MCF7 cells) treated with various hormone combinations. Results: In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. Importantly, when both hormones are present, progestin modulates estrogen action such that responsive transcriptomes, cellular processes and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Conclusions: Genomic Agonism and Phenotypic Antagonism between Estrogen and Progesterone Receptors in Breast Cancer. Individual and concerted actions of ER and PR highlight the prognostic and therapeutic value of PR in ER+/PR+ breast cancers. ER+/PR+ and ER+/PR-deficient model systems were deprived of steroids by culturing them in phenol red free RPMI 1640 media that is supplemented with 10% charcoal-stripped fetal bovine serum and 1% penicillin/streptomycin. Subsequently, these steroid-deprived models were treated with either vehicle, 10 nM estradiol, 10 nM progestin R5020 or 10 nM of both the hormones and genomics (ChIP-seq and RNA-seq) was performed. ChIP-seq was done after 45 minutes of hormone treatments. For cell models, RNA-seq was done after 12 hours of hormone treatments. Tumor explants were treated with either 24 or 48 hours.

2016-06-01 | E-GEOD-80367 | biostudies-arrayexpress

Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer. [tumor samples RNA-seq]

2016-06-01 | E-GEOD-80365 | biostudies-arrayexpress

Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer. [cell models RNA-seq]

2016-06-01 | E-GEOD-80366 | biostudies-arrayexpress

Unliganded Progesterone Receptor Governs Estrogen Receptor Gene Expression by Regulating DNA Methylation in Breast Cancer Cells

Project description:How breast cancers respond to endocrine therapy strongly depends on the expression of the estrogen and progesterone receptors (ER and PR, respectively), with doublenegative ER-/PR- breast cancers having worse clinical outcome than ER+/PR+ breast cancers. Although much is known about ERα gene (ESR1) regulation after hormonal stimulation, how it is regulated in the absence of hormones is not fully understood. We used ER+/PR+ positive breast cancer cells to investigate the role of PR in ESR1 gene regulation in the absence of hormones. We show that PR binds to the low-methylated ESR1 promoter and maintains both gene expression and the DNA methylation profile of the ESR1 locus in hormone-deprived breast cancer cells. Depletion of PR reduces ESR1 expression, with a concomitant increase in gene promoter methylation. The high amount of DNA methylation in the ESR1 promoter of PR-depleted cells persists after the stable re-expression of PR and inhibits PR binding to this genomic region. Consequently, the rescue of PR expression in PR-depleted cells is insufficient to restore ESR1 expression. Consistent with these data, DNA methylation impedes PR binding to consensus progesterone responsive elements in vitro. These findings help us understand the complex crosstalk between PR and ER, and suggest that the analysis of DNA methylation of ESR1 promoter in breast cancer cells can help to design the appropriate targeted therapies for different types of breast cancer patients.

2018-10-04 | GSE107966 | GEO

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