Transforming growth factor alpha and mouse models of human breast cancer

Transforming growth factor alpha (TGF alpha) is a principal molecule in the normal and neoplastic development of the mammary gland. Binding of TGF alpha to the epidermal growth factor receptor (EGFR), activates the EGFRs' endogenous tyrosine kinase activity and stimulates growth of the epithelium in the virgin and pregnant mouse mammary gland. TGF alpha expression can be detected in breast cancer cells in vivo and in vitro and overexpression can elicit partial transformation or immortalized human and rodent mammary epithelial cells. Despite evidence implicating TGF alpha in the development of mammary neoplasia, the actual mechanism of TGF alpha-induced transformation is unclear. Transgenic mouse models targeting heterologous TGF alpha to the mammary gland have established TGF alpha overexpression can induce hyperproliferation, hyperplasia and occasional carcinoma. These transgenic studies demonstrated a facilitating, proliferative role for TGF alpha in the development of neoplasia and implicated several oncogenes that can cooperate with TGF alpha to transform the mammary epithelium. From studies of EGFR signaling pathways, inhibitory and modulating agents such as anti-ECFR antibodies and specific kinases inhibitors have been used to block the action of this pathway and prevent the development of TGF alpha-induced neoplasia and tumor formation, Studies in Stat5a knockout mice have established that the JAK2/Stat5a pathway can facilitate the survival of the mammary epithelium and can impact the progression of TGF alpha-mandated mammary tumorigenesis, Together these experiments indicate that TGF alpha and the EGFR signaling pathway are potentially amenable to therapies for treatment of human breast disease.