In this project we propose to continue our ongoing work relating to how defective function of the BRCA1 gene results in breast cancer development. Specifically, we propose to ask the following questions. 1) Do specific molecular defects in the response to DNA double DNA strand breaks (DSB) exist in the tumor cells of sporadic basal like breast cancers(BLC)? BLC is a relatively common, BRCA 1 wt, phenocopy of BRCA1 mutant disease. If such defects exist, do any affect the operation of DSB response pathways to which BRCA1 normally makes a major contribution? 2) Is the BRCA1-IRIS protein, an alternatively spliced BRCA1 gene product, a protooncoprotein? If so, does its oncoprotein function contribute to the development of certain subtypes of sporadic breast cancer and, if so, how? 3) In a normal setting, BRCA 1 p220 is present and readily detectable in the nucleus both during the G1 and S/G2 cell cycle phases. It is less abundant in G1 than in S in some cell lines. Moreover, although it localizes after ionizing radiation (IR) in special nuclear foci (so called IRIF) in S/G2, it fails to do so in G1, even though these foci contain a protein (Rap80) that normally participates in tethering BRCA 1 to these structures. We seek to understand the molecular basis for this difference between G1 and S/G2 and, if deciphered, to probe its physiological significance, especially with respect to how it might relate to the normal regulation of BRCA1 DNA repair function.
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