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Estrogen Receptor and the Unfolded Protein Response: Double-Edged Swords in Therapy for Estrogen Receptor-Positive Breast Cancer

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Abstract

Estrogen receptor α (ERα) is a target for the treatment of ER-positive breast cancer patients. Paradoxically, it is also the initial site for estrogen (E2) to induce apoptosis in endocrine-resistant breast cancer. How ERα exhibits distinct functions, in different contexts, is the focus of numerous investigations. Compelling evidence demonstrated that unfolded protein response (UPR) is closely correlated with ER-positive breast cancer. Treatment with antiestrogens initially induces mild UPR through ERα with activation of three sensors of UPR—PRK-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6)—in the endoplasmic reticulum. Subsequently, these sensors interact with stress-associated transcription factors such as c-MYC, nuclear factor-κB (NF-κB), and hypoxia-inducible factor 1α (HIF1α), leading to acquired endocrine resistance. Paradoxically, E2 further activates sustained secondary UPR via ERα to induce apoptosis in endocrine-resistant breast cancer. Specifically, PERK plays a key role in inducing apoptosis, whereas IRE1α and ATF6 are involved in endoplasmic reticulum stress-associated degradation after E2 treatment. Furthermore, persistent activation of PERK deteriorates stress responses in mitochondria and triggers of NF-κB/tumor necrosis factor α (TNFα) axis, ultimately determining cell fate to apoptosis. The discovery of E2-induced apoptosis has clinical relevance for treatment of endocrine-resistant breast cancer. All of these findings demonstrate that ERα and associated UPR are double-edged swords in therapy for ER-positive breast cancer, depending on the duration and intensity of UPR stress. Herein, we address the mechanistic progress on how UPR leads to endocrine resistance and commits E2 to inducing apoptosis in endocrine-resistant breast cancer.

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Acknowledgments

The authors thank Don Norwood of Scientific Publications, Research Medical Library at the University of Texas MD Anderson Cancer Center for editing the manuscript.

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  1. Department of Breast Medical Oncology, Unit 1354, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas, TX 77030, USA

    Ping Fan & V. Craig Jordan

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  1. Ping Fan
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Correspondence to V. Craig Jordan.

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This work was supported by the Susan G. Komen for the Cure Foundation (SAC100009; to VC J), the NIH/NCI, under award number P30CA016672 (PW P), the Cancer Prevention Research Institute of Texas (the STARs and STARs plus awards; to VC J), the George and Barbara Bush Foundation for Innovative Cancer Research (to VCJ), and the benefactors of the Dallas/Fort Worth Living Legend Chair of Cancer Research (to VCJ).

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Ping Fan and V. Craig Jordan declared that they have no conflicts of interest that might be relevant to the contents of this article.

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Fan, P., Jordan, V.C. Estrogen Receptor and the Unfolded Protein Response: Double-Edged Swords in Therapy for Estrogen Receptor-Positive Breast Cancer. Targ Oncol 17, 111–124 (2022). https://doi.org/10.1007/s11523-022-00870-5

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