Abstract 4359: Rational development of novel treatment regimens to improve the efficacy of estrogen therapy in anti-estrogen-resistant ER+ breast cancer
Authors: Traphagen Nicole A. , Jiang Amanda , Hosford Sarah R. , Miller Todd W. 
Published: September 2020

Abstract
We hypothesize that the viability of estrogen receptor-positive (ER+) breast cancer cells that acquire resistance to anti-estrogens can be controlled through oscillation of ER stimulation and inhibition. Although anti-estrogen therapy has been highly successful in treating ER+ breast cancer, approximately one third of patients experience recurrent disease and progressively develop resistance to all available anti-estrogen therapies. Paradoxically, treatment with estrogens can elicit anti-cancer effects in tumors with acquired resistance to anti-estrogens. However, the clinical use of estrogen therapy is limited by the lack of a known mechanism of action and a predictive marker of response. In this study, we delineate the context-dependent effects of ER overexpression and use these results to rationally develop novel estrogen therapy treatment regimens to improve tumor response. Using cellular models of ER+ breast cancer, we demonstrate that ER overexpression is a mechanism of resistance to estrogen deprivation, resulting in estrogen-independent ER transcriptional activity. However, ER overexpression is also required for therapeutic response to estrogen. Upon treatment with the endogenous estrogen 17b-estradiol, ER overexpression results in hyperactivation of ER transcriptional activity, DNA damage, and subsequent cell death. DNA damage is ER-dependent, and cell death can be abrogated by knockdown of ER. Additionally, the combination of estrogen therapy with poly (ADP-ribose) polymerase (PARP) inhibition enhances DNA damage and cell death. Using a patient-derived xenograft (PDX) model of therapeutic response to 17b-estradiol, we serially profiled ER expression and transcriptional activity during treatment response and the subsequent development of treatment resistance. Tumors from mice treated with 17b-estradiol exhibit a phenotypic shift between sensitivity to estrogen therapy and estrogen deprivation therapy over the course of treatment. Based on these results, we developed novel treatment schedules and regimens to improve the anti-tumor effects of estrogen therapy. We demonstrate that short-term treatment with 17b-estradiol followed by estrogen deprivation can improve long-term anti-tumor effects, as compared to continuous treatment with 17b-estradiol. In conclusion, we demonstrate the differential effects of ER overexpression in estrogen-depleted vs. estrogen-replete environments, and translate this mechanistic understanding into novel treatment regimens to improve response to estrogen therapy.
Citation Format: Nicole A. Traphagen, Amanda Jiang, Sarah R. Hosford, Todd W. Miller. Rational development of novel treatment regimens to improve the efficacy of estrogen therapy in anti-estrogen-resistant ER+ breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4359.