Blocking cancer metastasis with TGF-beta antagonists

Abstract

I of epithelial-mesechymal transition (EMT) has been shown to confer both metastatic and self-renewal properties to breast tumor cells resulting in drug resistance and tumor recurrence. TGFβ is a potent inducer of EMT. We found that chemotherapeutic drug doxorubicin activates TGFβ signaling in breast cancer cells. Doxorubicin induced EMT, promoted invasion and enhanced stem cell properties in the murine 4T1 breast cancer cells in vitro, which were inhibited by a TGFβ type I receptor kinase inhibitor (TβRI-KI). Th ese observations suggest that the adverse activation of TGFβ pathway by chemotherapeutics in the cancer cells together with elevated TGFβ levels in tumor microenvironment may lead to EMT and generation of cancer stem cells resulting in the resistance to the chemotherapy. We investigated the potential synergistic anti-tumor activity of TβR1-KI in combination with doxorubicin in animal models of metastatic breast cancer. Combination of Doxorubicin and TβRI-KI enhanced the effi cacy 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 signifi cantly blocked when TβR1-KI was administered in combination with doxorubicin. Our results indicate that the combination treatment of doxorubicin with a TGFβ inhibitor has the potential to reduce the dose and consequently the toxic side-eff ects of doxorubicin, and improve its effi cacy in the inhibition of breast cancer growth and metastasis.