Doxorubicin in Combination with a Small TGFβ Inhibitor: A Potential Novel Therapy for Metastatic Breast Cancer in Mouse Models

Background: Recent studies suggested that induction of epithelial-mesenchymal transition (EMT) might confer both metastatic and self-renewal properties to breast tumor cells resulting in drug resistance and tumor recurrence. TGF beta is a potent inducer of EMT and has been shown to promote tumor progression in various breast cancer cell and animal models. Principal Findings: We report that chemotherapeutic drug doxorubicin activates TGF beta signaling in human and murine breast cancer cells. Doxorubicin induced EMT, promoted invasion and enhanced generation of cells with stem cell phenotype in murine 4T1 breast cancer cells in vitro, which were significantly inhibited by a TGF beta type I receptor kinase inhibitor (T beta RI-KI). We investigated the potential synergistic anti-tumor activity of T beta R1-KI in combination with doxorubicin in animal models of metastatic breast cancer. Combination of Doxorubicin and T beta RI-KI enhanced the efficacy of doxorubicin in reducing tumor growth and lung metastasis in the 4T1 orthotopic xenograft model in comparison to single treatments. Doxorubicin treatment alone enhanced metastasis to lung in the human breast cancer MDA-MB-231 orthotopic xenograft model and metastasis to bone in the 4T1 orthotopic xenograft model, which was significantly blocked when T beta R1-KI was administered in combination with doxorubicin. Conclusions: These observations suggest that the adverse activation of TGF beta pathway by chemotherapeutics in the cancer cells together with elevated TGF beta levels in tumor microenvironment may lead to EMT and generation of cancer stem cells resulting in the resistance to the chemotherapy. Our results indicate that the combination treatment of doxorubicin with a TGF beta inhibitor has the potential to reduce the dose and consequently the toxic side-effects of doxorubicin, and improve its efficacy in the inhibition of breast cancer growth and metastasis.