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Estrogen deprivation using aromatase inhibitors (AIs) has proven highly effective in the treatment of postmenopausal women with estrogen-receptor (ER)-positive breast cancer. Unfortunately, one of the consequences of long term estrogen deprivation (i.e. long-term use of AI) is the development of drug resistance (estrogen-independent growth). We have previously reported the development of a long-term estrogen deprived (LTED) breast cancer cell line (MCF-7:5C) which grows in the absence of estrogen but is sensitive to estrogen-induced apoptosis. In the present study, we used a Chemicon cell invasion assay kit to quantify cellular invasiveness of LTED cell. We found that MCF-7:5C cells along with another LTED cell line (MCF-7:2A) were highly invasive and more metastatic than wild-type MCF-7 breast cancer cells with the order of invasiveness being MCF-7:5C > MCF-7:2A > MCF-7. Microarray analysis of MCF-7:5C, MCF-7:2A, and MCF-7 breast cancer cells showed significant differences in the gene expression profiles between the cell lines with ~900 genes altered based on a change of twofold or greater. Invasion and metastatic genes such as carcinocinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), chemokine (C-X-C motif) receptor 4 (CXCR4), CD44, MMP3, and cadherins were dramatically upregulated in MCF-7:5C and MCF-7:2A cells compared to MCF-7 cells. In particular, CEACAM6 transcript was upregulated by 112-fold in MCF-7:5C cells and 21-fold in MCF-7:2A cells and its protein by 40-fold and 10-fold, respectively, relative to wild-type MCF-7 cells. Small interfering RNA (siRNA)-mediated downregulation of CEACAM6 expression in MCF-7:5C and MCF-7:2A cells dramatically reduced migration and invasion of these cells. Interestingly, we found that 17β-estradiol also blocked the invasiveness and migration of MCF-7:5C and MCF-7:2A cells and it downregulated CEACAM6 mRNA and protein expression in these cells. These findings identify CEACAM6 as a unique mediator of invasion and migration of aromatase inhibitor resistant breast cancer cells and suggest that it might be an important biomarker for metastasis and a possible target for treatment of patients with metastatic disease. This work is supported by the Department of Defense Breast Program under award number BC050277 Center of Excellence (Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense).

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA