A causative role of the membrane-bound tyrosine kinase ErbB-2 in breast tumorigenesis has been well established. MMTV/neu transgenic mice which overexpress ErbB-2 consistently develop mammary carcinomas with a high incidence. In human breast cancer, ErbB-2 is overexpressed in 25-30 of all cases and is representing a clinical marker of a poor prognosis. Besides to gene amplification, ErbB-2 overexpression has been attributed to transcription factors of the AP-2 family which were shown to control the ErbB-2 gene promoter in cell culture studies. Particularly AP-2alpha and gamma are often coexpressed in ErbB-2-positive breast carcinomas. However, LTRgamma transgenic mice which overexpress AP-2gamma in their mammary epithelium display only a very weak upregulation of the erbB-2 gene and do not develop mammary carcinoma. These findings therefore raise the possibility of functional cooperativity between both genes in breast cancer. To experimentally address the impact of AP-2gammaon ErbB-2-induced breast carcinogenesis we crossed MMTV/neu transgenic mice with LTRgamma transgenic mice and monitored tumor development in bitransgenic female progeny. AP-2gamma overexpression negatively influenced tumor incidence, as reflected by a reduced tumor number and a prolonged tumor latency. Histological analysis revealed three major types of tumors corresponding to different stages of tumor progression. Interestingly, an increased proportion of advanced stage carcinomas was observed in bitransgenic mice. Moreover, the AP-2gamma transgene differentially affected proliferation rates between the different progression stages: proliferation was enhanced at early stages but reduced in advanced stages in comparison to control tumors. Therefore, AP-2gamma while reducing the incidence of mammary tumors is promoting tumor progression.
Although transcription factors AP-2alpha and AP-2gamma have been implicated in the control of estrogen receptor (ER) and ErbB-2, their impact for breast cancer is still controversial. To better understand the role of AP-2 proteins in mammary neoplasia, the analysis of their spatial expression pattern in normal breast and breast cancer is required. A total of 51 specimens of female breast cancer patients and a tissue microarray containing 93 additional female breast cancer cases were immunohistochemically stained for AP-2alpha, AP-2gamma, ER and ErbB-2. In 70 cases of the tissue microarray, survival data comprising a period of up to 30 years were present. In non-neoplastic breast tissue, AP-2alpha was expressed in the inner glandular cell layer while AP-2gamma was expressed in the outer myoepithelial cell layer. Ductal carcinoma in situ revealed strongly AP-2alpha-positive tumor cells surrounded by a layer of AP-2gamma-positive myoepithelial cells. In invasive carcinoma, expression of AP-2alpha and AP-2gamma was variable. High expression of ER and AP-2alpha showed better survival rates than low expression of these markers. AP-2gamma expression had no effect on survival. These results for the first time reveal a distinct spatial expression pattern of AP-2alpha and AP-2gamma in normal breast and in ductal carcinoma in situ with specific AP-2gamma expression in myoepithelium. High ER and AP-2alpha expression in invasive breast cancer showed favorable survival rates. Therefore, AP-2alpha expression seems to be associated with better prognosis of breast cancer. AP-2gamma expression has no influence on survival reflecting that myoepithelial cells are not involved in the neoplastic process.
