Abstract P3-05-15: Divergent activation of AKT1 and AKT2 isoforms downstream of PI3K mutation impacts response of breast cancer cells to estradiol and PI3K inhibitors

Abstract

Abstract Background: PI3K mutations are observed in 30% of breast cancers, which are more common in estrogen receptor (ERα) positive breast cancers compared to ERα-negative breast cancers. AKT, a the major kinase downstream of PI3K, modulates ERα activity. It is unknown whether PI3K mutation leads to preferential activation of specific AKT isoform with ability to modulate ERα function. Results: We report elevated AKT1 but not AKT2 mRNA in breast cancers with PI3K mutation. Breast epithelial cells with targeted substitution of PI3K with PI3K-E545K or PI3K-H1047R demonstrated elevated AKT1_pS473 compared to AKT2_pS474, distinct AKT substrate phosphorylation, and enhanced Estrogen Receptor (ERα) activity. AKT1 had a dominant role in ERα:estradiol (E2)-dependent gene expression and proliferation. We have identified an unique gene expression signature in ERα-positive breast cancers that is dependent on ERα, estradiol (E2), AKT1, and the pioneer factor FOXA1. Elevated expression of this signature in ERα-positive tumor was associated with better response to endocrine therapy and outcome. In addition, AKT1 determined the sensitivity to PI3α-specific inhibitor BYL719 and pan-PI3K inhibitor BKM120. In contrast, AKT2 controlled global gene expression and elevated levels of an AKT2-directed protein signature predicted poor outcome in breast cancer patients. Conclusions: PI3K mutation favors AKT1 activation leading to imbalance in AKT isoform-specific kinome/proteome and an effect on specific signaling pathways, particularly ERα:E2 signaling network. Knowledge gained from this functional dissection of AKT isoform activity downstream of PI3K mutation can be exploited for therapeutic stratification, particularly for anti-estrogen and PI3K inhibitor-based therapies. Citation Format: Harikrishna Nakshatri, Chirayu Goswami, Sunil Badve, Luca Magnani, Mathieu Lupien, Poornima Bhat-Nakshatri. Divergent activation of AKT1 and AKT2 isoforms downstream of PI3K mutation impacts response of breast cancer cells to estradiol and PI3K inhibitors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-15.