ARHGAP15 in Human Breast Carcinoma: A Potent Tumor Suppressor Regulated by Androgens

Rho GTPase activating protein 15 (ARHGAP15) is a recently identified GTPase activating protein which enhances intrinsic hydrolysis of GTP-bound Ras-related C3 botulinus toxin substrate (Rac1), resulting in inactivation of Rac1. Although a lot of studies have pointed out the pivotal roles of the Rac1 pathway in the progression of breast carcinomas, the clinical significance of ARHGAP15 has remained largely unknown in human breast carcinomas. Therefore, we immunolocalized ARHGAP15 in one hundred breast carcinoma tissues. ARHGAP15 immunoreactivity was frequently detected in the cytoplasm of carcinoma cells, and was positively correlated with that of Rac1 and androgen receptor labeling index. Furthermore, ARHGAP15 immunoreactivity was significantly correlated with decreased risk of recurrence and improved prognosis, and multivariate analyses demonstrated that ARHGAP15 immunoreactivity was an independent prognostic factor for both disease-free and breast-cancer-specific survival of the patients. In addition, exogenous overexpression of ARHGA15 suppressed cell proliferation and migration of MCF-7 cells and SK-BR-3 cells. On the other hand, ARHGAP15 mRNA was significantly induced by dihydrotestosterone. These findings suggest that ARHGAP15 is an androgen-induced gene and has anti-tumorigenic roles associated with the Rac1 pathway. ARHGAP15 immunoreactivity is therefore considered a potent prognostic factor in human breast carcinomas.