Abstract 940: AR overexpression confers resistance to an aromatase inhibitor in ERα-positive breast cancer cells

Abstract

Abstract Background: Aromatase inhibitors (AIs) have emerged as the therapy of choice for the treatment of estrogen receptor alpha (ERα)-positive breast cancer. However, many patients develop resistance to AI treatment. Although the involvement of the ERα in AI resistance is well established, the role of the androgen receptor (AR) is not known. It has been estimated that about 60%-70% of ERα-positive breast cancer co-express the AR, and we have previously shown a role for AR-overexpression in tamoxifen resistance in ERα-positive MCF-7 breast cancer cells. Thus we hypothesized that AR overexpression might similarly be involved in resistance to the AI anastrazole (Anas). Materials and Methods: Stable transfection of MCF-7 cells was performed to generate cell lines that express the aromatase gene (MCF-7 BK Arom) and then co-transfected with an AR expression vector (MCF-7 AR Arom). Aromatase and AR expression levels were evaluated by western blot analysis. Proliferation was tested using anchorage independent soft agar assays and MTT in the presence of the androgen substrate androstenedione (AD), or AD plus Anas. ERα and AR transcriptional activities were tested with ERE-luciferase reporter assays. Results: Several clones expressing aromatase alone or aromatase plus AR were generated. MCF-7 aromatase clones overexpressing AR were resistant to the growth inhibitory effects of Anas when stimulated with the androgen AD. As expected AD treatment stimulated ERα transcriptional activity, but Anas was unable to block AD-stimulated activity in AR Arom-overexpressing cells. In addition, the growth of several of the AR Arom-overexpressing cells was stimulated with treatment of Anas alone. Resistance was not associated with activation of known mechanisms of resistance, such as HER2, or Akt activation. Inhibitors of various signaling and receptor growth pathways are currently being tested for their effects on blocking Anas resistance. Conclusion: Using a model of ERα-positive breast cancer cells expressing endogenous aromatase and AR, we have demonstrated that AR overexpression confers resistance to the AI Anas. 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 940. doi:10.1158/1538-7445.AM2011-940