Abstract 3890: TMPRSS2 serin protease is a novel biomarker for ER+ breast cancer patient prognosis and survival and mediates resistance to anti-estrogen treatment in ER+ breast cancer

Abstract

Abstract Breast cancer (BC) is the most commonly diagnosed cancer in women and the second leading cause of cancer related deaths in the US. About 70-80% of patients have ER+ BC and initially respond to anti-estrogen (ie, Tamoxifen) or endocrine/homonal treatments. However, about 60% of the patients inevitably develops resistance to anti-estrogen therapies (due to intrinsic (15-20%) and acquire resistance (30-40%), representing a major clinical problem, resulting in relapses and metastasis, leading to significant patient mortality. Therefore, understanding the underlying mechanisms causing resitance to hormonal or anti-estrogen treatments is needed the for developing highly effective threapies and improving patient survival. Cell surface proteases, including serine proteases, are proteolytic modifiers of particular targets, including growth factors and protease-activated receptors, which are critical for the activation of oncogenic signaling pathways. TMPRSS2, a member of type II transmembrane serine protease (TTSP) family, has been shown to be highly expressed in prostate cancer cells and its role in carcinogenesis. We found that TMPRSS2 is highly upregulated well established tamoxifene resistant cell lines derivative of MCF7 (LCC2 and LCC9) compared to MCF7 cells. Performing Kaplan-Meier survival analyses in TCGA-BC database we also found that TMPRSS2 expression is associated with poor prognosis and significantly shorter patient survival in ER+ BC patients (p=0.015, n=221 patients). In addition, we found that TMPRSS2 is regulated by Estrogen/Estrogen Receptor-alpha (ERα) signaling as in vitro inhibition of estrogen/ERα signaling by ERα siRNA, tamoxifen or faslodex reduced TMPRSS2 protein expression ER+ MCF7 BC cells. Moreover, we found that inhibition of TMPRSS2 by 3 different siRNA molecules suppressed cell proliferation of MCF7 cells and reduced expression critical proteins for cell cycle and proliferation, including cyclin D1, c-Myc and pERK/MAPK signaling, suggesting that TMPRSS2 promotes the oncogenic signaling pathways in ER+ BC cells. Currently, we are targeting TMPRSS2 in in vitro and in vivo Tamox-resistant LCC2 and LCC9 models in mice by siRNA alone and in combination with Tamoxifen or faslodex to demostrate inhibition of TMPRSS2 sensitize tumors to anti-estrogen treatments. In conclusion, TMPRSS2 is a potential biomarker for poor patient survival and anti-estrogen resistance, and targeting TMPRSS2 alone as a monothreapy and in combination with anti- Tamoxifen or faslodex may be a promising approach for overcoming resistance to estrogen thereapies in ER+ BC patients. Citation Format: Rumeysa Ozyurt, Nermin Kahraman, Pinar Atalay Dundar, Bulent Ozpolat. TMPRSS2 serin protease is a novel biomarker for ER+ breast cancer patient prognosis and survival and mediates resistance to anti-estrogen treatment in ER+ breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3890.