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Updated: Apr 15, 2026
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor
Neal D Andruska1, Xiaobin Zheng2, Xujuan Yang3
1Departments of Biochemistry, College of Medicine, and.
Abstract:
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 (IP3), which opens EnR IP3R 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 IP3R 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 therapy-resistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration.
Insights
A new drug, BHPI, effectively targets therapy-resistant estrogen receptor α-positive breast and ovarian cancers by inducing toxic endoplasmic reticulum stress and inhibiting protein synthesis, leading to tumor regression.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Recurrent estrogen receptor α (ERα)-positive breast and ovarian cancers often exhibit resistance to standard therapies.
- Estrogen receptor α (ERα) plays a critical role in the proliferation of these cancer cells.
- Existing therapies face challenges in overcoming drug resistance in ERα-positive cancers.
Purpose of the Study:
- To identify and characterize novel small molecule compounds that can selectively inhibit the proliferation of drug-resistant ERα-positive cancer cells.
- To elucidate the mechanism of action of a newly identified compound, BHPI, in targeting therapy-resistant ERα-positive cancers.
- To evaluate the therapeutic potential of BHPI in preclinical models of breast cancer.
Main Methods:
- High-throughput screening and functional validation assays were employed to identify BHPI.
- In vitro studies assessed BHPI's effect on cancer cell proliferation and ERα signaling.
- In vivo studies utilized a mouse xenograft model of breast cancer to evaluate tumor regression.
- Mechanistic studies investigated BHPI's impact on endoplasmic reticulum (EnR) stress, unfolded protein response (UPR), and protein synthesis.
Main Results:
- BHPI was identified as a potent noncompetitive small molecule ERα biomodulator.
- BHPI selectively blocked the proliferation of drug-resistant ERα-positive breast and ovarian cancer cells.
- BHPI induced rapid and substantial tumor regression in a mouse xenograft model.
- BHPI inhibits nuclear ERα-regulated gene expression and elicits sustained, toxic UPR activation by depleting ER Ca(2+) stores and inhibiting protein synthesis via PERK/eIF2α and eEF2 pathways.
Conclusions:
- BHPI demonstrates a novel mechanism of action by converting the UPR from a protective to a toxic response in ERα-positive cancer cells.
- BHPI's potent inhibition of protein synthesis and effectiveness against therapy-resistant tumors make it a promising candidate for further investigation.
- BHPI represents a potential new therapeutic strategy for treating drug-resistant ERα-positive breast and ovarian cancers.
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