Gene amplification of HER-2/neu is inversely correlated with loss of expression of the tetraspanin metastasis suppressor gene, KAI1/CD82, in breast cancer samples and cell lines
Introduction: Gene amplification of the proto-oncogene, HER-2/neu is associated with poor clinical outcome in women with breast cancer. High mortality rates are synonymous with high metastatic rates. The tetraspanin superfamily member, KAI1/CD82, is a metastasis suppressor gene whose expression is down-regulated in primary breast cancer tumors and lost in the corresponding axillary lymph node metastases. We hypothesized that there would be an inverse relationship between HER-2/neu gene amplification and loss of KAI1 expression in breast cancer tumors. Methods: The cell lines were obtained from UTSWMC and the ATCC. HER-2/neu status was evaluated by IHC, ELISA, and FISH. KAI1 protein expression was identified by a monoclonal antibody to KAI1. Pooled mRNAs from 5 HER-2/neu gene amplified vs. 5 non-amplified breast tumors were subjected to microarray analysis. Results: Among 7 non-HER-2/neu gene amplified cell lines, KAI1 expression was positive in 5 lines (71%). In contrast, only 1 of 6 HER-2/neu gene amplified lines were KAI1 positive (17%; p=0.05). In the 5 women with tumors that had HER-2/neu positive/KAI1 negative cell lines derived from their tumor specimens, a total of 75 of 90 dissected axillary lymph nodes were positive for metastases (83%). In contrast, 0 of 5 patients with HER-2/neu negative/KAI1 positive patients had axillary lymph node metastases (p=0.05). In a separate experiment, 5 pooled mRNAs from HER-2/neu gene amplified patient tumors were compared to those from 5 non-HER-2/neu gene amplified tumors. KAI1 was identified as the third most down-regulated gene among 5,500 genes and ESTs. Conclusions: Gene amplification of HER-2/neu was associated with loss of KAI1 expression in both patients samples and in cell lines. The combination of HER-2/neu gene amplification and loss of KAI1 expression was associated with a high number and high proportion of axillary lymph node metastases. We plan to further test our hypothesis in a larger data set with long-term clinical follow-up. If the inverse relationship persists, we will design a clinical trial to therapeutically address these molecular changes in women with tumors that have high metastatic potential.
Lombardi, DP; Wilson, KM; Michalopoulos, E; Conjeaud, H; Geradts, J
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