Rac1 activation in human breast carcinoma as a prognostic factor associated with therapeutic resistance.

Abstract

RAS-related C3 botulinus toxin substrate 1 (Rac1) is a molecular switch fluctuating between GDP-bound inactive form (Rac1-GDP) and GTP-bound active form (Rac1-GTP) and involved in diverse function in both normal and malignant cells such as breast carcinoma cells. Although several studies have demonstrated immunolocalization of Rac1 protein in human breast carcinoma tissues, activation status of Rac1 still remains to be elucidated. We immunolocalized active form of Rac1 (Rac1-GTP) as well as total Rac1 using antibody specific for them in 115 invasive breast carcinoma tissues and correlated with clinicopathological parameters and clinical outcomes. Rac1-GTP was frequently immunolocalized in the cytoplasm or cell membrane of breast carcinoma cells and it was positively correlated with Ki-67 labeling index and total Rac1 while negatively correlated with progesterone receptor. On the other hand, immunohistochemical Rac1-GTP status was significantly correlated with increased risk of recurrence and breast cancer-specific mortality of breast cancer patients and multivariate analyses did demonstrate Rac1-GTP as an independent worse prognostic factor for both disease-free and breast cancer-specific survival. In addition, Rac1-GTP was still correlated with worse prognosis in the patients who had received adjuvant chemotherapy or endocrine therapy. These findings suggested Rac1 activation played pivotal roles in the progression and therapeutic resistance of breast cancers and Rac1 might be an important therapeutic target for improvement of the therapy for breast cancer patients.