17β‐estradiol upregulates GREB1 and accelerates ovarian tumor progression <i>in vivo</i>

Laviolette, Laura A.; Hodgkinson, Kendra; Minhas, Neha; Perez‐Iratxeta, Carolina; Vanderhyden, Barbara C.

doi:10.1002/ijc.28741

Cited by 46 publications

(56 citation statements)

References 49 publications

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“…Consistent with previous reports that E2 promotes ovarian cancer cell growth (7,8,11), PEO1 and PEO4 cells were endocrine responsive in 2-D, 3-D, and ULA cultures. While PEO1 and PEO4 cells were isolated from the same patient (9), they exhibit different E2-response phenotypes.…”

Section: Discussionsupporting

confidence: 92%

Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens

Andersen

Sikora

Boisen

et al. 2017

Clinical Cancer Research

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Purpose High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha in ~80% of HGSOC and some small but promising clinical trials of endocrine therapy, estrogen receptor-alpha has been understudied as a target in this disease. We sought to identify hormone-responsive, estrogen receptor-alpha-dependent HGSOC. Experimental Design We characterized endocrine response in HGSOC cells across culture conditions (2-D, 3-D, forced suspension) and in patient-derived xenograft (PDX) explants, assessing proliferation and gene expression. Estrogen-regulated transcriptome data were overlapped with public datasets to develop a comprehensive panel of estrogen receptor-alpha target genes. Expression of this panel and estrogen receptor-alpha H-score were assessed in HGSOC samples from patients who received endocrine therapy. Time on endocrine therapy was used as a surrogate for clinical response. Results Proliferation is estrogen receptor-alpha-regulated in HGSOC cells in vitro and in vivo, and is partly dependent on 3-D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as estrogen receptor-alpha targets. The selective estrogen receptor-alpha down-regulator (SERD) fulvestrant is more effective than tamoxifen in blocking estrogen receptor-alpha action. Estrogen receptor-alpha H-score is predictive of efficacy of endocrine therapy, and this prediction is further improved by inclusion of target gene expression, particularly IGFBP3. Conclusions Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional ERα and endocrine responsiveness. Assessing ERα function (e.g. IGFBP3 expression) in conjunction with H-score may help select patients who would benefit from endocrine therapy. Preclinical data suggest that SERDs might be more effective than tamoxifen.

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Section: Discussionsupporting

confidence: 92%

Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens

Andersen

Sikora

Boisen

et al. 2017

Clinical Cancer Research

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“…Moreover, the up-regulation was abrogated by ER antagonist ICI 182, 780, suggesting ER requirement for this induction. It has previously reported that Cdh1, Cdh2 and Ctnnb1 were the established estrogen-targeting genes [22-26]. This was consistent with our observation in uterine epithelial cells.…”

Section: Discussionsupporting

confidence: 82%

“…Moreover, previous studies have found that Cdh1, Cdh2 and Ctnnb1 were the established estrogen-modulated genes [22-26]. In the in vitro cultured uterine epithelial cells, estrogen could also stimulate the expression of Cdh1, Cdh2 and Ctnnb1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Evidence For Hmgn2 Involvement in Mouse Embryo Implantation and Decidualization

Yue

Yang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Hmgn2 is involved in regulating embryonic development, but its physiological function during embryo implantation and decidualization remains unknown. Methods: In situ hybridization, real-time PCR, RNA interference, gene overexpression and MTS assay were used to examine the expression of Hmgn2 in mouse uterus during the pre-implantation period and explore its function and regulatory mechanisms in epithelial adhesion junction and stromal cell proliferation and differentiation. Results: Hmgn2 was primarily accumulated in uterine luminal epithelia on day 4 of pregnancy and subluminal stromal cells around the implanting blastocyst at implantation sites on day 5. Similar results were observed during delayed implantation and activation. Meanwhile, Hmgn2 expression was visualized in the decidua. In uterine epithelial cells, silencing of Hmgn2 by specific siRNA reduced the expression of adhesion molecules Cdh1, Cdh2 and Ctnnb1 and enhanced the expression of Muc1, whereas constitutive activation of Hmgn2 exhibited the opposite effects, suggesting a role for Hmgn2 in attachment reaction during embryo implantation. Estrogen stimulated the expression of Hmgn2 in uterine epithelia, but the stimulation was abrogated by ER antagonist ICI 182,780. Further analysis evidenced that attenuation of Hmgn2 might eliminate the regulation of estrogen on the expression of Cdh1, Cdh2 and Ctnnb1. In uterine stromal cells, progesterone induced the accumulation of Hmgn2 which advanced the expression of Prl8a2 and Prl3c1, two well-known differentiation markers for decidualization, but did not affect the proliferation of stromal cells. Knockdown of Hmgn2 blocked the progesterone-induced differentiation of uterine stromal cells. Moreover, Hmgn2 might serve as an intermediate to mediate the regulation of progesterone on Hand2. Conclusion: Hmgn2 may play an important role during embryo implantation and decidualization.

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“…Rs12331507 in Region I, which, other than Region A, had the greatest number of significant burden statistics, lies in an intergenic region approximately 20 kb upstream of KDR , a gene that encodes one of the two receptors for vascular endothelial growth factor (VEGF); VEGF has been shown to be expressed by tumor cells in ovarian cancer (31). Interestingly, the most significant SNP in Region C, rs142034631, is located in GREB1 , an estrogen-responsive gene that modulates tumor progression in models of ovarian cancer (32). …”

Section: Discussionmentioning

confidence: 99%

Evidence of a genetic link between endometriosis and ovarian cancer

Study

2016

Fertility and Sterility

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Objective To evaluate whether endometriosis-associated genetic variation affects risk of ovarian cancer Design Pooled genetic analysis Setting Research unit in a university hospital Patients/Animals Genetic data from 46,176 participants (15,361 ovarian cancer cases and 30,815 controls) from 41 ovarian cancer studies Intervention(s) None Main Outcome Measure(s) Endometriosis-associated genetic variation and ovarian cancer Results There was significant evidence of an association between endometriosis-related genetic variation and ovarian cancer risk, especially for the high-grade serous and clear cell histotypes. Overall, we observed 15 significant burden statistics, which was three times more than expected. Conclusion By focusing on candidate regions from a phenotype associated with ovarian cancer, we have shown a clear genetic link between endometriosis and ovarian cancer that warrants further follow-up. The functional significance of the identified regions and SNPs is presently uncertain, though future fine mapping and histotype-specific functional analyses may shed light on the etiologies of both gynecologic conditions.

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17β‐estradiol upregulates GREB1 and accelerates ovarian tumor progression in vivo

Cited by 46 publications

References 49 publications

Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens

Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens

Evidence For Hmgn2 Involvement in Mouse Embryo Implantation and Decidualization

Evidence of a genetic link between endometriosis and ovarian cancer

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