Abstract 2879: Mechanisms of integration for androgen receptor and phosphatidylinositol 3-kinase signaling in estrogen receptor negative class A breast cancer
Authors: Farnaz Jamshidi, Liying Zhang, Adriana Heguy, Ashley Doane, William Gerald, Jacqueline Bromberg, Clifford Hudis
Journal: Cancer Research (2011)

Abstract Effective targeted therapies for estrogen receptor-negative, progesterone receptor-negative breast cancer remains elusive. Previously, we identified a new subclass of ER- / PR- / AR+ breast cancers as Class A [1]. Class A breast cancer derived cell lines are growth inhibited by anti-androgens (bicalutamide) and stimulated by testosterone [1]. Interestingly, these cell lines harbor mutations in the PIK3CA gene leading to persistent activation of the PI3Kinase pathway [2,3]. In this report we examined the incidence of PIK3CA mutations in ER-/PR-/AR+ breast cancers. We also investigated the role of PI3K/AKT signaling on AR activity and growth of Class A cancer derived cell lines. We examined 100 primary ER-/PR- breast tumors and determined that 28% express AR by IHC. By Sequenom analysis we determined that 12% contain mutations in the PIK3CA gene within the canonical hot spots (exon 9,20). The expression of AR in ER- / PR- breast cancers positively correlated with PIK3CA mutations (p=0.0039), pAkt levels (p=0.01), and HER2 (p=0.05) expression. In addition, we observed a strong association between HER2 expression and pAkt levels in ER-/PR-/AR+ breast cancers. A number of in vitro studies were performed in order to examine the potential functional consequences of PI3K signaling in Class A breast cancer cell lines (MDA-MB-453 and HCC202). We first determined that the cell lines harboring PIK3CA mutations were more responsive to PI3K inhibitors for growth inhibition compared to class B cell lines (ER-,PR-,AR- breast cancer subclass [1]) lacking PIK3CA mutations. Induction of proliferation by synthetic androgen in class A breast cancer cell lines is decreased by androgen antagonist as well as PI3K inhibitors and the combination of both inhibitors had an additive effect. We also examined serine phosphorylated AR levels (a modification leading to enhanced AR transcriptional activity), AR transcriptional activity and the expression of AR target genes GGT1 and CYP4F8 in class A breast cancer cell lines. When cells were incubated with androgen agonists, the levels of all three elements were increased compared to vehicle control. Treatment with a PI3K inhibitor decreased the levels of all three elements compared to vehicle control. When cells were treated with the combination of the androgen agonist and a PI3K inhibitor, the levels of all three elements were higher than the inhibitor but lower than the agonist alone. These findings suggest that components of PI3K/AKT pathway can modulate AR activity suggesting a putative cross-talk between AR and PI3K pathways. This potential cooperative effect represents a new paradigm in targeted therapeutic strategies directed at the biological signal integration contributing to AR+ / ER- / PR- cancers. 1. Doane, A.S. Oncogene, 2006. 25(28): p. 3994 2. Kataoka, Y. Ann Oncol, 2010. 21(2): p. 255 3. Oda, K. Cancer Res, 2008. 68(19): p. 8127 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 2879. doi:10.1158/1538-7445.AM2011-2879