Abstract LB-269: PPARγ maintains ERBB2-positive breast cancer stem cells.

Abstract

Abstract Overexpression of the adverse prognostic marker ERBB2 occurs in 30% of breast cancers and is associated with aggressive disease and poor outcomes. Our recent findings have shown that NR1D1 and the peroxisome proliferator-activated receptor (PPAR) γ-binding protein (PBP) act through a common pathway in upregulating several genes in the de novo fatty acid synthesis network, which is highly active in ERBB2-positive breast cancer cells. NR1D1 and PBP are functionally related to PPARγ, a well-established positive regulator of adipogenesis and lipid storage. Here we report that inhibition of the PPARγ pathway reduces the ALDH positive population in ERBB2 positive breast cancer cells. Conversely, fatty acid synthase inhibitor C75 increases the fraction of ALDH-positive cells. In vitro tumorsphere formation assays demonstrate that the PPARg antagonist GW9662 decreases the tumorsphere formation in ERBB2-positive cells, but not other breast cells. We show that the mechanism by which GW9662 treatment causes a reduction in ALDH-positive population cells, is partially due to ROS, as it can be rescued by treatment with NAC. Furthermore, global gene expression analyses show that GW9662 treatment suppresses the expression of several lipogenic genes including ACLY, MIG12, FASN and NR1D1; and the stem cell related genes KLF4 and ALDH in BT474 cells. GW9662 also decreased the level of acetylation in histone 3 and histone 4 in BT474 cells, compared with MCF7 cells. In vivo, GW9662 pre-treatment inhibits the tumor-seeding ability of BT474 cells. Together, these results show that the PPARγ pathway is critical for the cancer stem cell properties of ERBB2 positive breast cancer cells. Citation Format: Xianhui Wang, Yan Sun, Jason Wong, Douglas Conklin. PPARγ maintains ERBB2-positive breast cancer stem cells. [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 LB-269. doi:10.1158/1538-7445.AM2013-LB-269