Abstract Prior to the advent of tamoxifen therapy, estradiol (E2) and the ER agonist, diethylstilbestrol, showed efficacy in the clinical in therapeutic treatment of breast cancer. The adverse effects of these therapeutic options led to discontinuation, despite tamoxifen itself sharing the adverse effect of uterine growth. The perceived therapeutic action of tamoxifen in countering the proliferative actions of E2 at the estrogen receptor (ER) in endocrine-sensitive breast tissues is not entirely compatible with the therapeutic actions of E2 itself in breast cancer, and points to a more complex role for ER. Tamoxifen is the standard of care for many patients with ER+ breast cancer; however significantly, 30-50% of women are resistant to tamoxifen therapy. Development of a Selective Estrogen Mimic (SEM) that is effective in breast cancer without uterotrophic and other side effects is a novel treatment option that we hypothesize will be effective in causing regression of tamoxifen-resistant breast cancer. We theorize that a rational approach would be an ER ligand with pharmacological partial agonist actions, thus able to mimic E2 in regressing breast cancer, but with antagonist actions in the face of excessive ER activation. Using the benzothiophene scaffold common to the clinical Selective Estrogen Receptor Modulators (SERMs), raloxifene and arzoxifene, we hypothesized that an ideal SEM could be designed by structural engineering. A library of over 30 compounds was developed and assayed in tamoxifen-resistant cell lines, including MCF-7 and T47D. One SEM was assayed in two mouse xenograft models and shown to cause tumor regression; impressively this SEM did not fuel growth of estrogen-dependent T47D xenografts and did not cause uterine growth. This SEM and several other compounds were observed to act as partial agonists at ERα, with variable actions at ERβ. To understand this phenomenon further, the contributions of apoptotic mechanisms and cell cycle arrest to SEM activity was studied in cell cultures. The results collected to date on SEMs that act as partial agonists at ERα indicate that this is a viable, new approach to breast cancer therapy. Citation Format: Gregory RJ Thatcher, Rui Xiong, Hitisha K Patel, Jiong Zhao, Xiao Liang, Yue-ting Wang, Mary Ellen Molloy, Debra Tonetti. Novel, non-uterotrophic, selective estrogen mimics cause regression of tamoxifen-resistant breast cancer in 2D and 3D cultures and in mouse xenograft models [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-23.