The AP-2 transcription factors are required for normal growth and morphogenesis during mammalian development. Previous in vitro studies have also indicated that the AP-2 family of proteins may be involved in the etiology of human breast cancer. The AP-2 genes are expressed in many human breast cancer cell lines, and critical AP-2-binding sites are present in both the ERBB-2 (HER2/neu) and estrogen receptor promoters. We have now characterized immunological reagents that enable specific AP-2 family members, including AP-2α and AP-2γ, to be detected in human breast cancer epithelium. Data obtained with these reagents demonstrate that whereas AP-2α and AP-2γ are both present in benign breast epithelia, there is a significant up-regulation of AP-2γ expression in breast cancer specimens (P = 0.01). There was also a significant correlation between the presence of the AP-2α protein and estrogen receptor expression (P = 0.018) and between specimens containing both AP-2α/AP-2γ proteins and ERBB-2 expression (P = 0.003). Furthermore, we detected an association (P = 0.04) between the expression of AP-2γ and the presence of an additional signal transduction molecule implicated in breast cancer, the insulin-like growth factor I receptor. Analysis of the proximal promoter of the insulin-like growth factor I receptor revealed a novel AP-2-binding site. Thus, AP-2 proteins may directly regulate the transcription of this growth factor receptor. Taken together, these data strongly support a role for the AP-2 gene family in the control of cell growth and differentiation in breast cancer.

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Supported by the Yale University School of Medicine Department of Therapeutic Radiology, ACS-IRG Award IN31-38 (to T. W.), American Cancer Society Grant RPG-98-096-01-MGO (to T. W.), and NIH Grant RO1 CA 77833 (to T. W.), B. C. T. is an AACR-AFLAC Scholar. J. Z. is the recipient of a breast cancer research fellowship from the Department of the Army (DAMD17-96-1-6094).

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