The primary objective of this project ultimately is to develop strategies that specifically kill breast cancer cells. The adenoviral oncoprotein E1A serves as a tool to understand how both normal and tumor cells become chemosensitive. E1A confers chemosensitivity and p53 potentiates E1A function. Signaling to p53 involves the p19ARF tumor suppressor gene. Furthermore, at least two functions within the N-terminal region of E1A are required to confer chemosensitivity and stabilize p53 in normal cells. One of these functions is to inactivate the retinoblastoma gene product and ElA mutants unable to inactivate Rb but retaining the second N-terminal function selectively promote chemosensitivity in cells lacking an intact Rb pathway. The second N-terminal function correlates with E1As ability to bind the p400TRRAP complex, occurring independently of binding p300CBP. This function is a myc-like function as c-myc also binds the p400TRRAP complex, and c-myc can specifically synergize to fully restore chemosensitivity with an ElA mutant unable promote apoptosis or bind p400. Ongoing studies to further elucidate the mechanism of how ElA enhances chemosensitivity may provide a pathway to target that improves the likelihood of successfully treating breast cancer.