The AP-2 family of transcription factors provide novel molecular tools to dissect the mechanisms of gene expression in the normal development of the mammary gland and in breast cancer. The AP-2 proteins are present in breast cancer biopsies and have been implicated in the expression of several breast cancer markers, including c-erbB-2 and the estrogen receptor. Furthermore, one of the AP-2 gene family members, AP-2 gamma, maps to a chromosomal locus which is frequently altered in human breast cancer.

AP-2 genes are critical regulators of many aspects of vertebrate embryonic development, including formation of the neural tube and body wall. In contrast, the importance of these transcription factors for normal mammary gland development, or for breast cancer, has not yet been examined. As a first step in this analysis, a comprehensive understanding of the expression of the AP-2 genes throughout normal growth and maturation of the mouse mammary gland will be determined. In addition, the incidence of AP-2 in breast cancer biopsies will be examined and compared to the expression of other markers, including c-erbB-2. Taken together, these studies will; assess if the expression of AP-2 is a predisposing factor in breast cancer; address the potential importance of AP-2 as a diagnostic or prognostic indicator; and indicate the feasibility of using the AP-2 proteins as targets for gene therapy.

The AP-2 genes will also be utilized to probe mouse mammary gland development. First, the cis-acting sequences and trans-acting factors regulating AP-2 expression in the mammary gland will be identified. This analysis will utilize a region of the AP-2 promoter which directs gene expression to the developing mammary gland. This analysis will reveal not only the molecular mechanisms of mammary gland development but also how AP-2 expression is regulated in breast tumor tissue. In a second approach, animal model systems will be generated in which the expression of AP-2 in the mammary gland has been altered. These transgenic and knockout mice will be examined to ascertain if the inappropriate expression of AP-2 can influence normal mammary gland development and breast cancer.

R01CA077833

1998-05-01

2004-02-29