Abstract 805: The role of aldo-keto reductases and estrogen signalling in acquired anthracycline resistance

Abstract Breast cancer is the second leading cause of death from cancer in North American women. The disease can be difficult to treat by adjuvant or neoadjuvant chemotherapy because of intrinsic or acquired resistance to chemotherapy agents. To better understand the mechanisms for acquired resistance to the anthracycline class of chemotherapy agents in breast cancer, a series of MCF-7 breast tumour cell lines have been developed that exhibit progressive resistance to epirubicin (MCF-7EPI cells) or to doxorubicin (MCF-7DOX2 cells). Following mRNA microarray analysis, several genes were identified whose expression was associated with the acquisition of anthracycline resistance. Among these were several Aldo-keto Reductases (AKRs) responsible for estrogen synthesis from estrone and anthracycline detoxification to 13-hydroxymetabolites. AKR 1C3 showed more than a 10-fold increase in expression in anthracycline-resistant breast tumour cells. We hypothesized that the over-expression of AKR 1C3 would lead to both increased drug detoxification and an increase in estrogen synthesis. This would result in increased tumour cell survival and growth in the presence of anthracyclines. Recently, we observed that estrogen levels were, in fact, increased as cells became anthracycline-resistant. In contrast, the expression of estrogen receptor ≤ (ESR1) was reduced by 2- to 5-fold at the gene level and 2- to 20- fold at the protein level, with a concomitant reduction in the estrogen-dependent expression of Bcl-2 and Cyclin D1. Diminished Bcl-2 and cyclin D1 expression would be expected to reduce the growth rate of the cells, a hypothesis we have confirmed in cell culture experiments. Taken together, our findings suggest that selection for anthracycline resistance in breast tumour cells results in alterations in AKR expression, resulting in enhanced detoxification of doxorubicin, the promotion of estrogen biosynthesis, and the reduced estrogen-dependent expression of Bcl-2 and cyclin D1. The reduced expression of Bcl-2 and cyclin D1 blunts the growth rate of anthracycline-resistant cells, which would further increase the ability of these cells to survive in the presence of anthracyclines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 805. doi:1538-7445.AM2012-805