Abstract 1236: Novel androgen receptor inhibitors in triple negative breast cancer
Authors: Bhattacharya Saswati , Cai Yuanqi , Kurina Steven , Westmark Pamela , Hokanson Benjamin , Anderson Matthew , O’Regan Ruth 
Published: July 2017

Triple negative breast cancer (TNBC), which lacks expression of hormone receptors and human epidermal growth factor receptor 2, has the worst prognosis of all breast cancer subtypes, due to inherent chemo-resistance and a lack of therapeutic targets. A subset of TNBC has been shown to express androgen receptor (AR) but despite promising pre-clinical data, clinical trials evaluating the use of approved anti-androgens (bicalutamide, enzalutamide) in AR-positive TNBC has shown modest efficacy to date. In prostate cancer, bicalutamide binds to AR with low affinity and in the presence of AR gene amplification or mutation, can exhibit partial agonist activity leading to resistance. In order to increase affinity for AR and to avoid AR antagonist to agonist conversion synthesized 7-substituted umbelliferones (UMB) derivatives with a distinct scaffold modified from available AR antagonists (Kandil et al Bioorganic & Medicinal Chemistry Letters, 2016). These agents exhibited inhibitory activity in human prostate cancer cells lines at sub-micro molar level, a 50-fold and 30-fold improvement over bicalutamide and enzalutamide, respectively. We hypothesized that these novel AR antagonists would be effective in inhibiting the growth of AR-positive TNBC cells. Methods: TNBC AR negative mesenchymal MDA-MB-231 (as control) and AR positive MDA-MB-231 cells were utilized for determination of the efficacy of the UMB derivatives. For proliferation assays, viability of the cells was monitored over a period of 72 hours with redox dye Cell Titer-Blue. Standard Western blotting techniques were used for protein detection. For apoptosis analysis, standard flow cytometry reagents, FITC labelled Annexin V and Propidium Iodine(PI) mix were utilized. Results: UMB derivatives decreased the expression of AR in AR-positive MDA-MB-453 in a dose dependent manner. UMB derivatives, at micro Molar concentration decreased cell proliferation of AR-positive and interestingly AR-negative cell lines by 20 to 50%, also in a dose dependent manner. UMB derivatives induced apoptosis in both cell lines. Interestingly, UMB derivatives induced a change from a mesenchymal to epithelial phenotype in AR-negative MDA-MB-231 cells, which was confirmed by decreased expression of vimentin and other mesenchymal markers. Conclusions: Novel UMB derivatives inhibit growth and cause apoptosis in TNBC cells and induce mesenchymal-to-epithelial transition in an AR-negative mesenchymal TNBC cell line. Targeting AR with novel AR antagonists seem to be a promising therapeutic approach for AR-positive TNBC and further evaluation of AR antagonists in AR-negative mesenchymal TNBC is warranted.

Citation Format: Saswati Bhattacharya, Yuanqi Cai, Steven Kurina, Pamela Westmark, Benjamin Hokanson, Matthew Anderson, Ruth O’Regan. Novel androgen receptor inhibitors in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1236. doi:10.1158/1538-7445.AM2017-1236