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Review
. 2019 Dec:152:108493.
doi: 10.1016/j.steroids.2019.108493. Epub 2019 Sep 10.

ERα-targeted endocrine therapy, resistance and the role of GPER

Richard A Pepermans  1 , Eric R Prossnitz  2
Affiliations
Review

ERα-targeted endocrine therapy, resistance and the role of GPER

Richard A Pepermans et al. Steroids. 2019 Dec.

Abstract

Endocrine therapy is an effective option for the treatment of estrogen receptor alpha (ERα)-positive breast cancers. Unfortunately, a large fraction of women relapse with endocrine-resistant tumors. The presence of constitutively active ERα mutants, found in a subset of relapse tumors, is thought to be an important endocrine resistance mechanism and has prompted the search for more effective anti-hormone drugs that can effectively inhibit these mutant versions of the receptor. The G protein-coupled estrogen receptor (GPER) is also thought to contribute to the development of endocrine resistance, in part, due to its activation by clinically used selective estrogen receptor modulators and downregulators (SERMs/SERDs). Therefore, next-generation drugs should be screened for potential activity towards GPER. Here, we highlight the need for truly ERα-selective SERMs and SERDs that do not cross-react with GPER for the treatment of ERα-positive breast cancers.

Keywords: Breast cancer; ERα; Endocrine resistance; GPER; SERD; SERM.

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Conflict of interest statement

Conflicts of interest

E.R.P. is an inventor on U.S. Patent Nos. 7,875,721 and 8,487,100 for GPER-selective ligands and imaging agents and U.S. Patent No. 10,251,870 and pending patents for applications of GPER-selective ligands.

Figures

Figure 1.
Figure 1.
Structures of the SERMs tamoxifen, toremifene and raloxifene and the SERD fulvestrant.
Figure 2.
Figure 2.
Structures of the AIs exemestane, anastrozole and letrozole.
Figure 3.
Figure 3.
Structures of the currently in-development orally bioavailable SERDs AZD9496, LSZ102, GDC-0927, ZB716 and the orally bioavailable SERM bazedoxifene.
Figure 4.
Figure 4.. Proposed role of GPER in the development of endocrine resistance.
Tamoxifen (as well as other SERMs and SERDs) inhibits its molecular target (ERα) (red line), but simultaneously cross-activates GPER (green arrow). This cross-activation induces the downstream activation of Akt and other survival signals. Chronic cross-activation of GPER by tamoxifen (over the course of the average 5 year tamoxifen regimen) provides a subset of primary tumor cells with prolonged survival signaling that opposes the inhibitory cell death induced through the tamoxifen-mediated inhibition of ERα. Prolonged survival thus provides this subset of surviving primary tumor cells sufficient time to acquire additional mutations that lead to resistance to the primary therapy, resulting in the development of endocrine-resistant relapse tumors.
See this image and copyright information in PMC

References

    1. Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA, Mechanisms of estrogen action, Physiological reviews 81(4) (2001) 1535–65. - PubMed
    1. Jensen EV, DeSombre ER, Estrogen-receptor interaction, Science 182(4108) (1973) 126–34. - PubMed
    1. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA, Cloning of a novel receptor expressed in rat prostate and ovary, Proceedings of the National Academy of Sciences of the United States of America 93(12) (1996) 5925–30. - PMC - PubMed
    1. Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER, A transmembrane intracellular estrogen receptor mediates rapid cell signaling, Science 307(5715) (2005) 1625–30. - PubMed
    1. Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA, International Union of Pharmacology. LXIV. Estrogen receptors, Pharmacological reviews 58(4) (2006) 773–81. - PubMed

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