Abstract 547: Inhibition of PI 3-K isoforms lead to reactivation of Akt signaling in a subset of breast cancer cell lines.

Abstract

Abstract The aggressive behavior of malignant breast cancer cells is determined by a complex array of signaling pathways that regulate functions such as growth, survival, and migration. Production of phosphatidylinositol-3,4,5-P3 (PIP3) by phosphoinositide 3-kinase (PI 3-K) results in activation of downstream targets including the protein kinase Akt that plays critical roles in cell survival and growth. Recent studies have highlighted alternate, PI 3-K independent pathways often associated with malignancy that lead to Akt reactivation. The goal of our studies is to investigate the role of PI 3-K catalytic subunits in Akt reactivation in breast cancer. Surprisingly, knock-down of the catalytic subunit of class I PI 3-K PIK3CA actually enhances phosphorylation of Akt, as well as the downstream targets S6K1 and GSK3β in a subset of triple negative breast cancer (TNBC) cell lines. The resulting increase in Akt phosphorylation is mTORC2-dependent and is insensitive to the class I PI 3-K inhibitors. Rescue experiments with wild type PIK3CA alleles reveal a further enhancement of Akt phosphorylation, when compared to PIK3CA knock-down alone. Moreover, silencing of distinct class I subunits PIK3CB and PIK3CD also enhanced Akt phosphorylation in TNBC. However, this effect is not universal and is not observed in numerous other breast cancer cell lines, or using specific PIK3CA inhibitors. This reactivation of Akt signaling suggests the interruption of a feedback loop similar to the mTOR-S6K-IRS1 negative feedback loop. It also indicates specific roles for individual PI 3-K isoforms in breast cancer and dependent on the mutational status of PTEN and PIK3CA. This research is supported by Susan G. Komen for the Cure postdoctoral fellowship KG111139 to EC and AT. Citation Format: Emilie Collmann, Alex Toker. Inhibition of PI 3-K isoforms lead to reactivation of Akt signaling in a subset of breast cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 547. doi:10.1158/1538-7445.AM2013-547