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 alp ha to the epidermal growth factor receptor (EGFR), activates the EGFRs' end ogenous tyrosine kinase activity and stimulates growth of the epithelium in the virgin and pregnant mouse mammary gland. TGF alpha expression can be d etected in breast cancer cells in vivo and in vitro and overexpression can elicit partial transformation or immortalized human and rodent mammary epit helial 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 th e mammary gland have established TGF alpha overexpression can induce hyperp roliferation, hyperplasia and occasional carcinoma. These transgenic studie s demonstrated a facilitating, proliferative role for TGF alpha in the deve lopment of neoplasia and implicated several oncogenes that can cooperate wi th TGF alpha to transform the mammary epithelium. From studies of EGFR sign aling pathways, inhibitory and modulating agents such as anti-ECFR antibodi es and specific kinases inhibitors have been used to block the action of th is pathway and prevent the development of TGF alpha-induced neoplasia and t umor formation, Studies in Stat5a knockout mice have established that the J AK2/Stat5a pathway can facilitate the survival of the mammary epithelium an d can impact the progression of TGF alpha-mandated mammary tumorigenesis, T ogether these experiments indicate that TGF alpha and the EGFR signaling pa thway are potentially amenable to therapies for treatment of human breast d isease.