Molecular targeting of Bcl-xL during chemotherapy-induced tumor dormancy can inhibit breast cancer relapse

Abstract

Breast cancer (BCa) mortality is mainly due to distant recurrence of the disease associated with the establishment of tumor dormancy following initially successful treatment of early-stage breast cancer. Current clinical practice for cancer survivors is a “wait and watch” approach without any therapeutic or relapse preventing interventions, except for ER-positive BCa patients who receive hormone therapy, yet remain at risk of tumor recurrences. In attempt to identify a molecular target in dormant tumor cells, we discovered upregulation of Bcl-xL in chemotherapy-induced dormant tumor cells. To target such survival pathway in FVBN202 transgenic mouse model of neu-overexpressing breast cancer, we first established tumor dormancy by means of a low dose immunogenic chemotherapy (FAC, 5-FU + Adriamycin + Cyclophosphamide) of the neu-overexpressing mouse mammary carcinoma (MMC) while using a specific inhibitor of Bcl-xL, A-1331852. Such combination therapy in vitro resulted in the inhibition of chemotherapy-induced tumor relapse. In addition, selective knockdown of Bcl-xL in MMC by means of shRNA prevented relapse of chemotherapy-induced dormant tumor cells. Our findings suggest tumor-targeted delivery of A-1331852 during chemotherapeutic treatment of early-stage breast cancer for the prevention of distant recurrences of the disease.