Regulation of RUNX1 by androgen receptor, a new potencial mechanism of TNBC progression

Natalia B Fernández¹, Sofía M Sosa¹, Justin T Roberts², Jennifer K Richer³, Natalia Rubinstein¹

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype for which no effective targeted therapies are available. Growing evidence suggests that chemotherapy-resistant cancer cells with stem-like properties (CSC) may repopulate the tumor. Therefore, therapies that target the CSC in combination with chemotherapy might prevent tumor recurrence. Androgen Receptor (AR) is expressed in at least half of all TNBC. AR inhibition decreases CSC in vitro and tumor initiation in vivo. RUNX1 correlates with poor prognosis in TNBC patients. Our group has shown that RUNX1 promotes TNBC cell migration and regulates tumor gene expression, like RSPO3 and GJA1. Our goal is to investigate the role of RUNX1 in the TNBC-RA+. Here we show that RUNX1 mRNA and protein expression is upregulated by treatment with DHT (AR agonist) in MDA-MB-453 cells, and that this effect is blocked in the presence of Enzalutamide (AR antagonist). ChIP-seq experiments revealed AR binding to RUNX1 regulatory regions in MDA-MB-453 cells, suggesting a direct regulation. Also, RUNX1 inhibition by AI-10-104 (a synthetic drug) produced a reduction in MDA-MB-453 and BT-549 cell proliferation and an enhancement in treatment sensibility. It has been reported that AR inhibition combined with chemotherapy result in more effective than chemotherapy alone in vitro and in vivo. In line with this, RUNX1 inhibition could be a potential target to also potentiates the anti-tumor effect of AR inhibition.