Abstract 865: Fat-1 gene suppression of breast cancer growth in mice

Abstract

Abstract The high ratio of n-6/n-3 polyunsaturated fatty acids (PUFAs) content in Western diets (approximately 10 to 30) may be related to the high breast cancer rate in the United States compared to Japan (approximately 4). Numerous studies in literature report about the tumor suppression effect of n-3 PUFAs, a main component of fish or fish oil. A recent study on B16 melanoma on C57BL/6 mice carrying the fat-1 gene, suppressed the melanoma by changing the n-6/n-3 ratio in tumors from 27:1 in wild type mice to 4.6:1 in fat-1 mice. In this project, a fat-1 gene, which encodes a fatty acyl desaturase that acts on substrates of 16-20 carbons and converts n-6 to n-3 fatty acids, was transfected into the human breast cancer cells MDA-MB-231, parental MCF-7 and tamoxifen-resistant MCF-7/TAM-R cells, Sk-BR3 and murine EMT6 mammary tumor cells. Both fat-1 transgenic mice and fat-1 gene treated breast cancer cells were employed to test our hypothesis that fat-1 suppresses the growth of both estrogen receptor (ER) positive and ER negative breast cancer cells that respond poorly to endocrine therapies. We have also treated the breast cancer cell lines with docosahexaenoic acid (DHA, n-3 fatty acid), arachidonic acid (AA, n-6 fatty acid) with a vehicle control. We found that for the ER negative human breast cancer cells, MDA- MB-231 and SK-BR-3 cells, the cell proliferation rate of DHA treated cells decreased 50%, compared to the corresponding control cells treated with AA and vehicle control. The fatty acid analysis of the fat-1 gene expressing breast cancer cells MDA-MB-231 and MCF-7 showed 30% and 46% reduction of n-6/n-3 ratio, respectively, and ∼30% reduction of cell proliferation rate. The fat-1 transfected MDA-MB-231 cells have ∼4-fold increase of cell apoptosis by Tunel assay. Fat-1 gene expression also suppresses the growth of tamoxifen resistant human breast cancer cells MCF-7F/Tam-R. These results indicate that fat-1 or n-3 fatty acid suppresses breast cancer cells in an ER independent way. Normal human mammary epithelial cells treated with DHA, AA and BSA showed no significant difference of growth rates, suggesting that the n-3 suppression effect is breast cancer selective. In a preliminary study, the growth rate of the EMT6 mammary tumors were significantly reduced when the cell line was treated with fat-1 gene before inoculation into the FVB/NJ mice. The transgenic mice expressing fat-1 gene are also used to investigate the breast cancer suppression effect of fat-1 gene in vivo. The underlying mechanism of the breast cancer suppression effect by fat-1 gene is currently under investigation. This study may provide a potential adjuvant therapeutic method for hormonal resistant human breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 865. doi:10.1158/1538-7445.AM2011-865