Abstract P1-12-01: Prevention of BRCA1-associated mammary cancers by selective progesterone receptor modulators (SPRM) in mice
Authors: Lee Oukseub , Sun Limin , Bosland Maarten C. , Wang Minhua , Shidfar Ali , Hosseini Omid , Helenowski Irene , Clare Susan E. , Khan Seema A. 
Published: March 2020

Background: It was previously demonstrated that mifepristone (MFP), an SPRM with anti-glucocorticoid receptor (GR) activity, blocks mammary tumor formation in a BRCA1 deficient mouse model (deletion of exon 11). We sought to compare tumor prevention efficacy of MFP with other SPRMs having less GR binding, using a different BRCA1 deficient mouse model (deletion of exon 22-24). We also compared the efficacy of multiple SPRMs on suppression of cell proliferation (Ki67) in benign mammary glands, to evaluate early effects in unaffected glands.

Methods: At 4-months-old, the female mice (Blg_Cre Brca1 f22-24/f22-24; p53+/-) were randomized to four treatment groups (n= 14-21 per group): no treatment control, MFP, telapristone acetate (TPA), and ulipristal acetate (UPA) and treated subcutaneously with a pellet containing 30mg of drug. Pellets were replaced every 90 days. The mice were monitored for tumor formation and growth until 15- months of age. When the tumor burden of mice became 1 cm2 or at age 15-months, the mice were euthanized to collect tumors and mammary glands for histopathologic evaluation. Ki67 and PR expression in mammary tissues were measured by immunohistochemistry and images were analyzed by ImageJ/Fiji software. Total RNA extracted from benign and tumor tissue was sequenced to discover SPRM-modulated genes and molecular pathways, in comparison with no-treatment controls.

Results: The occurrence of invasive cancers (adenocarcinoma) was similar in MFP-treated and control mice in a time-adjusted analysis (72% of MFP group vs. 74% of controls, p= 0.55). TPA-treated mice displayed a non-significant lower tumor incidence (56 %) compared to control group (p=0.11). However, UPA-treated mice showed significantly less tumor incidence (43%) than controls (p=0.04). These results were supported by suppression of %Ki67 labeling Index (LI) of benign glands. Median %Ki67 LI of benign glands of tumor-affected mice were: controls (18%) = MFP (18%) &gt; TPA (16%) &gt; UPA groups (10 %). Median Ki67% LI of benign glands of tumor-unaffected mice were: MFP (16%) &gt; TPA (13%) &gt; controls (12%) &gt; UPA group (6%). Reduction of cell proliferation by UPA was significant in benign glands of tumor-affected and un-affected mice compared to controls (p=0.007 for both) while reductions in the MFP and TPA groups were not significant. All of the invasive cancers were PR negative; PR is expressed in abnormal and benign lesions adjacent to invasive adenocarcinoma. To determine whether PR expression is related to tumor progression, we are evaluating PR expression in both benign and abnormal glands from all mice. Furthermore, RNA sequencing is underway to determine genes differentially expressed by UPA and MFP treatment compared to no treatment.

Conclusions: Our mouse model (BRCA1 Δexon22-24) displayed a spectrum of sensitivity to the three SPRMs we have tested: UPA&gt;TPA&gt;MFP, UPA showing higher potency than TPA. The reason for the lack of efficacy of MFP may relate to its strong affinity to GR, resulting in mixed effects on both PR and GR as a reason for its failure in this model. Understanding mechanisms underlying the different anti-tumor efficacy of UPA and MFP in our model will provide important insights that will aid the clinical development of PR-directed strategies for breast cancer prevention in both BRCA1 mutation carriers.

Citation Format: Oukseub Lee, Limin Sun, Maarten C. Bosland, Minhua Wang, Ali Shidfar, Omid Hosseini, Irene Helenowski, Susan E. Clare, Seema A. Khan. Prevention of BRCA1-associated mammary cancers by selective progesterone receptor modulators (SPRM) in mice [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-12-01.