RUNX1 Is Regulated by Androgen Receptor to Promote Cancer Stem Markers and Chemotherapy Resistance in Triple Negative Breast Cancer
Natalia B. Fernández,
Sofía M. Sosa,
Justin T. Roberts,
María S. Recouvreux,
Luciana Rocha-Viegas,
Jessica L. Christenson,
Nicole S. Spoelstra,
Facundo L. Couto,
Ana R. Raimondi,
Jennifer K. Richer,
Natalia Rubinstein
Affiliations
Natalia B. Fernández
Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina
Sofía M. Sosa
Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina
Justin T. Roberts
Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL 36688, USA
María S. Recouvreux
Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina
Luciana Rocha-Viegas
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Godoy Cruz 2290, Buenos Aires C1425FQB, Argentina
Jessica L. Christenson
Department of Pathology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Nicole S. Spoelstra
Department of Pathology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Facundo L. Couto
Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina
Ana R. Raimondi
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Godoy Cruz 2290, Buenos Aires C1425FQB, Argentina
Jennifer K. Richer
Department of Pathology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Natalia Rubinstein
Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina
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. The androgen receptor (AR) is expressed in up to 50% of TNBCs, and AR inhibition decreases CSC and tumor initiation. Runt-related transcription factor 1 (RUNX1) correlates with poor prognosis in TNBC and is regulated by the AR in prostate cancer. Our group has shown that RUNX1 promotes TNBC cell migration and regulates tumor gene expression. We hypothesized that RUNX1 is regulated by the AR and that both may work together in TNBC CSC to promote disease recurrence following chemotherapy. Chromatin immunoprecipitation sequencing (ChIP-seq) experiments in MDA-MB-453 revealed AR binding to RUNX1 regulatory regions. RUNX1 expression is upregulated by dihydrotestosterone (DHT) in MDA-MB-453 and in an AR+-TNBC HCI-009 patient-derived xenograft (PDX) tumors (p p < 0.05). Inhibition of RUNX1 transcriptional activity reduced the expression of CSC markers. Interestingly, RUNX1 inhibition reduced cell viability and enhanced paclitaxel and enzalutamide sensitivity. Targeting RUNX1 may be an attractive strategy to potentiate the anti-tumor effects of AR inhibition, specifically in the slow-growing CSC-like populations that resist chemotherapy which lead to metastatic disease.
