Expression of AP-2 transcription factors in human breast cancer correlateswith the regulation of multiple growth factor signalling pathways

The AP-2 transcription factors are required for normal growth and morphogen esis during mammalian development. Previous itt vitro studies have also ind icated 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 canc er 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 im munological reagents that enable specific AP-2 family members, including AP -2 alpha and AP-2 gamma, to be detected in human breast cancer epithelium. Data obtained with these reagents demonstrate that whereas AP-2 alpha and A P-2 gamma are both present in benign breast epithelia, there is a significa nt up-regulation of AP-2 gamma expression in breast cancer specimens (P = 0 .01), There was also a significant correlation between the presence of the AP-2 alpha protein and estrogen receptor expression (P = 0.018) and between specimens containing both AP-2 alpha/AP-2 gamma proteins and ERBB-2 expres sion (P = 0.003), Furthermore, we detected an association (P = 0.04) betwee n the expression of AP-2 gamma and the presence of an additional signal tra nsduction molecule implicated in breast cancer, the insulin-like growth fac tor I receptor. Analysis of the proximal promoter of the insulin-like growt h factor I receptor revealed a novel AP-2-binding site. Thus, AP-2 proteins may directly regulate the transcription of this growth factor receptor. Ta ken together, these data strongly support a role for the AP-2 gene family i n the control of cell growth and differentiation in breast cancer.