The liver receptor homolog-1 regulates estrogen receptor expression in breast cancer cells

Thiruchelvam, Paul; Lai, Chun‐Fui; Hua, Hui; Thomas, Ross S; Hurtado, Antoni; Hudson, William Henry; Bayly, Andrew R.; Kyle, Fiona; Periyasamy, Manikandan; Φωτίου, Α.; Spivey, Alan C.; Ortlund, Eric A.; Whitby, Richard J.; Carroll, Jason S.; Coombes, R. Charles; Buluwela, Laki; Ali, Simak

doi:10.1007/s10549-010-0994-9

Cited by 71 publications

(76 citation statements)

References 40 publications

(22 reference statements)

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“…Annicotte et al reported that the human LRH-1 promoter contains a near-perfect palindromic oestrogen response element (ERE) [74], to which ER␣ binds to stimulate promoter activity. This is consistent with the observed correlation between LRH-1 mRNA levels and ER␣ status in a variety of breast cancer cell lines [74], as well as the known positive association between LRH-1 positivity and ER␣ status in primary human breast carcinoma [11,81]. Knockdown of LRH-1 expression with siRNA in MCF-7 cells inhibits the proliferative effect of oestrogen [74], suggesting that the mitogenic effects of oestrogen may be mediated, in part, via LRH-1.…”

Section: Breast Cancersupporting

confidence: 87%

Therapeutic potential of Liver Receptor Homolog-1 modulators

Lazarus¹,

Wijayakumara²,

Chand³

et al. 2012

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Breast Cancersupporting

confidence: 87%

Therapeutic potential of Liver Receptor Homolog-1 modulators

Lazarus¹,

Wijayakumara²,

Chand³

et al. 2012

The Journal of Steroid Biochemistry and Molecular Biology

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“…10), these probes could be used as molecular tools for deciphering the roles of LRH-1 in different cellular contexts. For example, previous research demonstrated that selective blocking of LRH-1 function by either receptor-specific siRNA or genetic manipulations results in inhibition of growth and proliferation of cancerous cells expressing the receptor; the latter include breast (20,21) and colon (17) cancer as well as pancreatic adenocarcinoma cells (24). The analogous, anti-proliferative effects have been observed for the epithelial cells of intestinal crypts in mice with loss-of-function mutation in the LRH-1 gene (9).…”

Section: Discussionmentioning

confidence: 89%

“…11, E and F). Previous independent studies demonstrated that disabling of LRH-1 by either receptor-specific siRNA or genetic manipulations results in inhibition of growth and proliferation of breast (20,21) and colon (17) cancer cells. Complementing these findings, our work reveals that proliferation rates of both breast and colon carcinoma cells are significantly compromised following treatments with LRH-1 antagonists (corresponding concentrations of compounds associated with ϳ50% inhibition of cell proliferation are indicated in Fig.…”

Section: Tablementioning

confidence: 99%

“…The established transcriptional targets of LRH-1 paired with ␤-catenin include CCND1 and CCNE1 genes as well as MYC genes known for controlling cell differentiation, growth, and proliferation (6,7,9). Because these developmental pathways and associated genes are re-activated during tumorigenesis (11)(12)(13)(14)(15)(16), an aberrant activity of LRH-1 is linked to different types of malignancies, including breast and endometrial cancers as well as intestinal tumors and cancer of the pancreas (17)(18)(19)(20)(21)(22)(23)(24). The LRH-1 recep-tor is also implicated in development of various metabolic disorders related to insufficient liver and pancreas functions (25)(26)(27).…”

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confidence: 99%

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Structure-based Discovery of Antagonists of Nuclear Receptor LRH-1

Benod

Carlsson

Uthayaruban

et al. 2013

Journal of Biological Chemistry

100

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Background: Liver receptor homolog 1 (LRH-1, NR5A2) regulates functions of liver, intestines, and pancreas; its aberrant activity is associated with tumorigenesis. Results: Our work identifies the first antagonists of LRH-1. Conclusion:The identified ligands inhibit LRH-1 transcriptional activity, diminishing expression of the receptor's target genes. Significance: LRH-1 inhibitors could be used for analyses of the receptor's biological mechanisms and for development of cancer therapeutics.

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“…Noncompetitive ERα inhibitors targeting this unmet therapeutic need, including DIBA, TPBM, TPSF, and LRH-1 inhibitors that reduce ERα levels, show limited specificity, require high concentrations (>5 μM), and usually have not advanced through preclinical development (9)(10)(11)(12). These noncompetitive ERα inhibitors and competitor antiestrogens are primarily cytostatic and act by preventing estrogen-ERα action; therefore, they are largely ineffective in therapy-resistant ERα containing cancer cells that no longer require estrogens and ERα for growth.…”

mentioning

confidence: 99%

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

Andruska¹,

Zheng²,

Yang³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

140

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Recurrent estrogen receptor α (ERα)-positive breast and ovarian cancers are often therapy resistant. Using screening and functional validation, we identified BHPI, a potent noncompetitive small molecule ERα biomodulator that selectively blocks proliferation of drug-resistant ERα-positive breast and ovarian cancer cells. In a mouse xenograft model of breast cancer, BHPI induced rapid and substantial tumor regression. Whereas BHPI potently inhibits nuclear estrogen-ERα-regulated gene expression, BHPI is effective because it elicits sustained ERα-dependent activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), and persistent inhibition of protein synthesis. BHPI distorts a newly described action of estrogen-ERα: mild and transient UPR activation. In contrast, BHPI elicits massive and sustained UPR activation, converting the UPR from protective to toxic. In ERα + cancer cells, BHPI rapidly hyperactivates plasma membrane PLCγ, generating inositol 1,4,5-triphosphate (IP 3 ), which opens EnR IP 3 R calcium channels, rapidly depleting EnR Ca 2+ stores. This leads to activation of all three arms of the UPR. Activation of the PERK arm stimulates phosphorylation of eukaryotic initiation factor 2α (eIF2α), resulting in rapid inhibition of protein synthesis. The cell attempts to restore EnR Ca 2+ levels, but the open EnR IP 3 R calcium channel leads to an ATP-depleting futile cycle, resulting in activation of the energy sensor AMP-activated protein kinase and phosphorylation of eukaryotic elongation factor 2 (eEF2). eEF2 phosphorylation inhibits protein synthesis at a second site. BHPI's novel mode of action, high potency, and effectiveness in therapyresistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration.estrogen receptor | drug discovery | breast cancer | unfolded protein response | ovarian cancer E strogens, acting via estrogen receptor α (ERα), stimulate tumor growth (1-3). Approximately 70% of breast cancers are ERα-positive and most deaths due to breast cancer are in patients with ERα + tumors (2, 4). Endocrine therapy using aromatase inhibitors to block estrogen production, or tamoxifen and other competitor antiestrogens, often results in selection and outgrowth of resistant tumors. Although 30-70% of epithelial ovarian tumors are ERα-positive (1), endocrine therapy is largely ineffective (5-7). After several cycles of chemotherapy, tumors recur as resistant ovarian cancer (5), and most patients die within 5 years (8).Noncompetitive ERα inhibitors targeting this unmet therapeutic need, including DIBA, TPBM, TPSF, and LRH-1 inhibitors that reduce ERα levels, show limited specificity, require high concentrations (>5 μM), and usually have not advanced through preclinical development (9-12). These noncompetitive ERα inhibitors and competitor antiestrogens are primarily cytostatic and act by preventing estrogen-ERα action; therefore, they are largely ineffective in therapy-resistant ERα containing cancer cells that no longer requi...

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The liver receptor homolog-1 regulates estrogen receptor expression in breast cancer cells

Cited by 71 publications

References 40 publications

Therapeutic potential of Liver Receptor Homolog-1 modulators

Therapeutic potential of Liver Receptor Homolog-1 modulators

Structure-based Discovery of Antagonists of Nuclear Receptor LRH-1

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

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