Biomedical Sciences ETDs

Publication Date

Summer 7-1-2019

Abstract

Estrogen plays multiple roles in health and disease, exerting its effects through the classical estrogen receptors (ERα and ERβ) and the G protein‑coupled estrogen receptor (GPER). Current ER‑targeting ligands, including the therapeutic ERα antagonist tamoxifen, have been shown to cross‑activate GPER. This cross‑activation is hypothesized to contribute to clinically observed endocrine resistance in breast cancer, highlighting the potential benefit of truly ER‑selective antagonists. We report the identification of a novel class of ER‑selective ligands that lack cross‑reactivity towards GPER, identifying a truly ER‑selective agonist (AB‑1) and antagonist (AB‑82P). Importantly, AB‑82P degrades a clinically relevant ERα mutant and exhibits inhibitory effects in cellular models of endocrine resistance. This novel class of ER‑selective ligands can aid in improving our understanding of the individual estrogen receptors in estrogen biology and more importantly, provide a structural basis for the development of new, truly ER‑selective antagonists for the treatment of ERα‑positive breast cancers.

Keywords

ERα, GPER, Estrogen, Endocrine Resistance, Breast Cancer

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Eric Prossnitz, PhD

Second Committee Member

Helen Hathaway, PhD

Third Committee Member

Laurie Hudson, PhD

Fourth Committee Member

Angela Wandinger-Ness, PhD

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