Chemotherapeutic Targeting of the Transforming Growth Factor-β Pathway in Breast Cancers

Transforming growth factor (TGF-β) is a multifunctional cytokine that plays essential roles in regulating mammary gland development, morphogenesis, differentiation, and involution. TGF-β also regulates mammary gland homeostasis and prevents its transformation by prohibiting dysregulated cell cycle progression, and by inducing apoptosis; it also creates cell microenvironments that readily inhibit cell migration, invasion, and metastasis. Interestingly, while early-stage mammary tumors remain sensitive to the tumor suppressing activities of TGF-β, late-stage breast cancers become insensitive to the anticancer functions of this cytokine and instead rely upon TGF-β to drive disease and metastatic progression. This switch in TGF-β function is known as the "TGF-β Paradox" and represents the rationale for developing chemotherapies to inactivate the TGF-β pathway and its oncogenic functions in late-stage breast cancers. Here we outline the molecular mechanisms that manifest the "TGF-β Paradox" and discuss the challenges associated with the development and use of anti-TGF-β agents to treat breast cancer patients.