Abstract 2430: Aromatase expression inhibits anoikis and promotes bone metastasis of ERα positive breast cancer cells

Abstract

Abstract Aromatase is the rate-limiting enzyme that catalyzes the final step in estrogen biosynthesis. In postmenopausal women the ovary ceases to make estrogen. Although it has been shown that estrogen is produced locally in breast cancer (BCa) tissue of postmenopausal women for the proliferation and survival of ERα (+) BCa cells, there is little information on the role and the regulation of aromatase in breast cancer cells for their survival when they intravasate into the circulation where estrogen level is very low. Human breast cancer CAMA-1 cell along with aromatase-transfected MCF-7 (MCF-7/Aro) and ZR-75-1 (ZR-75-1/Aro/CL10) cells were cultured in suspension to mimic circulating tumor cells. Interestingly, all the three ERα(+) BCa cell lines expressed more aromatase in suspension culture compare to the adhesion culture. Moreover both endogenous and transfected aromatase were upregulated in suspension culture. Additionally, a higher expression of ERα was also observed in suspension culture, which could increase the sensitivity of the breast caner cells to intracrine estrogen. We found that anoikis was shown to be inhibited by the supplementation of testosterone, which is converted to estradiol by aromatase. Conversely, addition of the aromatase inhibitor letrozole blocked the testosterone-induced anoikis inhibition. The increase of pro-apoptotic protein BAX and BAD were observed in suspension culture, while the treatment of estrogen inhibited the expression of BAX and BAD in both adhesion culture and suspension culture. More interestingly, mice with intracardiacally inoculated ZR-75-1/Aro cells presented distant bone metastasis in the mandible and tibiae/femora after 2-weeks of inoculation without estrogen supplement, while the control ZR-75-1 cells were incapable of forming metastasis without estrogen. Our findings provide an important foundation for future investigation on how hormone-dependent BCa cells survive in circulation during the process of metastasis. 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 2430. doi:10.1158/1538-7445.AM2011-2430