Search

Summary 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 2530 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-2a and ? are often coexpressed in ErbB-2-positive breast carcinomas. However, LTR? transgenic mice which overexpress AP-2? 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-2?on ErbB-2-induced breast carcinogenesis we crossed MMTV/neu transgenic mice with LTR? transgenic mice and monitored tumor development in bitransgenic female progeny. AP-2? 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-2? 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-2? while reducing the incidence of mammary tumors is promoting tumor progression. [ABSTRACT FROM AUTHOR]

The role of HER-2/neu in male breast cancer is not well defined. The purpose of the current study was to measure the frequency of HER-2/neu expression in primary male breast cancer, to demonstrate HER-2/neu gene amplification in cases found to be positive for protein overexpression, and to correlate HER-2/neu positivity with clinicopathological variables. Formalin-fixed, paraffin-embedded archival material from 99 primary male breast carcinomas was evaluated by immunohistochemistry (IHC) using the HercepTest™ (DAKO Corp., Hamburg, Germany). Scoring was performed according to established guidelines. All cases demonstrating HER-2/neu staining by IHC (1+/2+ and 3+) were analyzed for HER-2/neu gene amplification by fluorescence in situ hybridization (FISH) utilizing the PathVysion™ assay (Vysis Corp., Downers Grove, Illinois) to assess HER-2/neu amplification status. The immunohistochemical staining of the HER-2/neu protein revealed HER-2/neu positivity in 15/99 (15.1%) cases, eight tumors showed 2+ and 7 tumors 3+ staining. HER-2/neu gene amplification was observed in 11/99 cases (11,1%), and all of the 3+ and 4/8 from the 2+ cases were amplified. HER-2/neu gene amplification/protein overexpression did not correlate with tumor state, histological grade or estrogen/progesterone receptor status nor the axillary lymph node status. This is the first comprehensive study of HER-2/neu gene amplification by FISH analysis in primary male breast cancer. Compared to female primary breast cancer the percentage of HER-2/neu positivity in our study was lower. Our data provide first evidence for HER-2/neu gene amplification in male breast cancer. Further studies should be addressed on the potential application of the monoclonal rhuMAB HER-2/neu antibody for treatment of HER-2/neu positive male breast cancer. [ABSTRACT FROM AUTHOR]