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Tissue Specific Pathways for Estrogen Regulation of Ovarian Cancer Growth and Metastasis

ABSTRACT: Menopausal estrogen (E2) replacement therapy increases the risk of estrogen receptor (ER)-positive epithelial ovarian cancers (EOC). Whether E2 is tumorigenic or promotes expansion of undiagnosed pre-existing disease is unknown. To determine E2 effects on tumor promotion, we developed an intraperitoneal mouse xenograft model using ZsGreen fluorescent ER- 2008 and ER+ PEO4 human EOC cells. Tumor growth was quantified by in vivo fluorescent imaging. In ER+ tumors, E2 significantly increased size, induced progesterone receptors, and promoted lymph node metastasis, confirming that ER are functional and foster aggressiveness. Laser captured human EOC cells from ER- and ER+ xenografted tumors were profiled for expression of E2-regulated genes. Three classes of E-regulated EOC genes were defined, but less than 10% were shared with E-regulated breast cancer genes. Since breast cancer selective ER modulators (SERM) are therapeutically ineffective in EOC, we suggest that our EOC-specific E-regulated genes can assist pharmacologic discovery of ovarian targeted SERM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22600 | GEO | 2011/05/13

SECONDARY ACCESSION(S): PRJNA128381

REPOSITORIES: GEO

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Tissue Specific Pathways for Estrogen Regulation of Ovarian Cancer Growth and Metastasis

Project description:Menopausal estrogen (E2) replacement therapy increases the risk of estrogen receptor (ER)-positive epithelial ovarian cancers (EOC). Whether E2 is tumorigenic or promotes expansion of undiagnosed pre-existing disease is unknown. To determine E2 effects on tumor promotion, we developed an intraperitoneal mouse xenograft model using ZsGreen fluorescent ER- 2008 and ER+ PEO4 human EOC cells. Tumor growth was quantified by in vivo fluorescent imaging. In ER+ tumors, E2 significantly increased size, induced progesterone receptors, and promoted lymph node metastasis, confirming that ER are functional and foster aggressiveness. Laser captured human EOC cells from ER- and ER+ xenografted tumors were profiled for expression of E2-regulated genes. Three classes of E-regulated EOC genes were defined, but less than 10% were shared with E-regulated breast cancer genes. Since breast cancer selective ER modulators (SERM) are therapeutically ineffective in EOC, we suggest that our EOC-specific E-regulated genes can assist pharmacologic discovery of ovarian targeted SERM. 15 samples were included in this experiment with a 2x2 factorial design with 2 different cell lines (2008 and PEO4) and 2 different hormone treatments (E for Estrogen and C for Placebo Control) and 4 replicates per treatment. 1 sample was excluded (a replicate of PEO4 with C treatment) because of poor quality.

2011-05-13 | E-GEOD-22600 | biostudies-arrayexpress

Endometrial profile of low-dose estradiol and tamoxifen combination therapy

Project description:Combination therapy with estrogen and a selective estrogen receptor modulator (SERM) is a promising approach to safely alleviate important side effects related to estrogen deficiency in women at high risk for breast cancer. Data related to endometrial safety of estrogen+SERM co-therapies are limited, however. The primary goal of this study was to evaluate the endometrial profile of low-dose E2 and Tam alone and in combination. In this study 16 postmenopausal female cynomolgus macaques were randomized to receive placebo, low-dose micronized estradiol (E2, 0.25 mg/1800 kcal), the SERM tamoxifen (Tam, 20 mg/1800 kcal), or E2+Tam in a parallel-arm design. Endometrial samples were collected after 4 months of treatment and used for microarray analysis.

2010-05-06 | E-GEOD-14518 | biostudies-arrayexpress

Transcriptomic analysis of the estrogenic effect of soy protein isolate in rat uterus

Project description:There are concerns regarding possible reproductive toxicity from consumption of soy including an increased risk of endometriosis and endometrial cancer. We used global uterine gene expression profiles in adult ovariectomized (OVX) female rats assessed by RNAseq to examine the estrogenicity of soy protein isolate (SPI) and the potential for feeding SPI to alter estrogen signaling in the uterus. Rats were fed AIN93G diets made with casein (CAS) or SPI from postnatal day (PND) 30. Rats were OVX on PND 50 and infused with 17 beta-estradiol (E2) or vehicle. E2 increased uterine wet weight (P<0.05) and significantly altered expression of 2084 uterine genes. In contrast, SPI feeding had no effect on uterine weight and only altered expression of 177 genes. Overlap between E2 and SPI genes was limited to 69 genes (3%). GO analysis indicated significant differences in uterine biological processes affected by E2 and SPI and little evidence for recruitment of ER alpha to the promoters of ER-responsive genes after SPI feeding. The major E2 up-regulated uterine pathways were cancer pathways and extracellular organization. SPI feeding up-regulated uterine PPAR signaling and fatty acid metabolism. The combination of E2 and SPI feeding resulted in significant regulation of 715 fewer genes relative to E2 alone. In a separate experiment, the combination of E2 and SPI reversed the ability of E2 to induce uterine proliferation in response to the carcinogen dimethybenz(a)anthracene (DMBA). These data suggest SPI does not act as a weak estrogen in the uterus but appears to be a selective estrogen receptor modulator (SERM) interacting with a small sub-set of E2-regulated genes and to be anti-estrogenic in the presence of endogenous estrogens. Rat uterus mRNA of ovariectomized adult female rats subject to four different diets (Caseine, Caseine + E2, Soy and Soy+E2 ) were sequenced, in triplicate, in an Illumina GAIIx sequencer.

2015-06-13 | E-GEOD-69819 | biostudies-arrayexpress

ATAC-seq of MCF-7 cells post ligand treatment

Project description:Goal: study the impact of estrogen receptor ligands on chromatin accessibility in MCF-7 cells Methods: Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq) Results: Ligand 4-OH tamoxifen, a selective ER modulator (SERM), significantly alters chromatin accessibility and partially mimics the effect of natural ligand E2 on chromatin accessibility in MCF-7 breast cells. Selective ER degraders (SERD) fulvestrant and GDC-0927 on the other hand have very little impact on chromatin accessibility.

2019-07-25 | GSE117940 | GEO

Endometrial profile of low-dose estradiol and tamoxifen combination therapy

2009-02-03 | GSE14518 | GEO

Transcriptomic analysis of the estrogenic effect of soy protein isolate in rat uterus

2015-06-13 | GSE69819 | GEO

RNA-seq of breast cancer cell lines post ligand treatment II

Project description:Goal: study the impact of estrogen receptor ligands on gene expression in HR+ breast cancer cells Methods: RNA sequencing Results: Ligand 4-OH tamoxifen, a selective ER modulator (SERM), promotes transcriptional activation of ER and mimics the transcriptional effect of natural ligand E2 for a subset of ER target genes, consistently across the seven breast cell lines (MDA-MB-134 VI, MDA-MB-330, EFM-19, T-47D, and BT-474). Selective ER degraders (SERD) fulvestrant and GDC-0927 on the other hand do not induce, or induce very weakly the expression of ER target genes. The effect of GDC-0810 depends on the cellular context.

2019-07-25 | GSE128911 | GEO

RNA-seq of breast cancer cell lines post ligand treatment I

Project description:Goal: study the impact of estrogen receptor ligands on gene expression in HR+ breast cancer cells Methods: RNA sequencing Results: Ligand 4-OH tamoxifen, a selective ER modulator (SERM), promotes transcriptional activation of ER and mimics the transcriptional effect of natural ligand E2 for a subset of ER target genes, consistently across the seven breast cell lines (MCF-7, HCC1500, MDA-MB-330, EFM-19, T-47D, BT-474, and CAMA-1). Selective ER degraders (SERD) fulvestrant and GDC-0927 on the other hand do not induce, or induce very weakly the expression of ER target genes. The effect of GDC-0810 depends on the cellular context.

2019-07-25 | GSE117942 | GEO

ERα-CtBP-mediated repression of Homologous-recombination repair in ovarian cancer improves chemo-sensitivity [ChIP-seq]

Project description:Deficiency in homologous recombination repair (HRR) is frequently associated with hormone-responsive cancers. Epithelial ovarian cancer (EOC) is a typical hormone-related tumor, with defects of HRR in up to half of cases. However, whether there are molecular connections between estrogen signaling and HRR deficiency in EOC remains unknown. Here we report an inverse correlation between estrogen signaling and HRR activity in EOC. Genome-wide mapping of ERα reveals ERα co-bindings with co-repressor CtBP, especially on many HRR gene loci, in EOC cells but not in breast cancer cells. Consistently, depleting ERα in EOC cells up-regulates HRR activity and HRR gene expression. Importantly, estrogen signaling enhances the sensitivity of ovarian cancer cells to chemotherapy agents in vitro and in vivo. Large-scale analyses further indicate that estrogen replacement and ERα expression are associated with favorable survival of EOC patients. These findings characterize a novel role of ERα in mediating the molecular connection between hormone and HRR in EOC, and suggest that estrogen signaling may improve the treatment outcome of EOC patients.

2019-06-26 | GSE116005 | GEO

ERα-CtBP-mediated repression of Homologous-recombination repair in ovarian cancer improves chemo-sensitivity [RNA-seq]

2019-06-26 | GSE115481 | GEO

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