The androgen receptor regulates Runx1, a new potential way to target chemotherapy resistant triple negative breast cancer

NATALIA FERNÁNDEZ; SOFÍA MARÍA SOSA; JUSTIN ROBERTS; JENNIFER RICHER; NATALIA RUBINSTEIN

Buenos Aires

Congreso; LXVI Reunión Anual de la Sociedad Argentina de la Investigación Clínica (SAIC); 2021

Triple negative breast cancer (TNBC) is an aggressive breast cancer (BC) subtype for which no effective targeted therapies are available. Growing evidence suggests that chemotherapy-resistant BC 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 is regulated by AR in prostate cancer. In TNBC patients, RUNX1 protein levels correlate with poor prognosis. Our group has shown that RUNX1 promotes TNBC cell migration and regulates tumor gene expression, such as the oncogene RSPO3. Also, by RUNX1 ChIP assays, we found SOX4 as a potential target gene. We hypothesized that RUNX1 is regulated by AR and that both may work together in TNBC CSCs to promote persistence and disease recurrence following chemotherapy. Here we show that, in MDA-MB-453 cells, RUNX1 expression is upregulated by dihydrotestosterone, an AR agonist, and that this effect is blocked in the presence of Enzalutamide (AR antagonist). ChIP-seq experiments revealed AR binding to RUNX1 regulatory regions, suggesting direct regulation. RUNX1 expression is increased in a CSC-like experimental model and responds to AR activity. Inhibition of RUNX1 transcriptional activity by AI-10-104 (a synthetic drug) reduced the expression of the CSC marker SOX4. Interestingly, this inhibition drives a reduction of MDA-MB-453 and BT-549 cell proliferation and enhanced paclitaxel sensitivity. It was reported that AR inhibition combined with chemotherapy results in a more effective outcome than chemotherapy alone in vitro and in vivo. In sum, RUNX1 inhibition may also be an attractive target to potentiate the anti-tumor effect of AR inhibition, specifically in the slow growing CSC-like populations that resist chemotherapy and lead to metastatic disease.