Abstract P4-09-01: Tumor suppressor control of the cancer stem cell angiogenic niche

Abstract

Abstract Mammary stem cells (MSC) expansion is associated with aggressive human breast cancer. The nuclear receptor peroxisome proliferator activated receptor γ (PPARγ) is a breast cancer tumor suppressor, but the mechanisms of this suppression are not completely characterized. To determine if PPARγ regulates MSC expansion in mammary cancer, we deleted PPARγ expression in the mammary epithelium of an in vivo model of basal breast cancer. Loss of PPARγ expression reduced tumor latency, and expanded the CD24+/CD49fhi MSC population. PPARγ null mammary tumors exhibited increased angiogenesis which was detected in human breast cancer. In vivo inhibition of a PPARγ regulated miR-15a/angiopoietin-1 pathway blocked increased angiogenesis and MSC expansion. PPARγ bound and activated a canonical response element in the miR-15a gene. PPARγ null tumors were sensitive to the targeted anti-angiogenic drug sunitinib but resistant to cytotoxic chemotherapy. Normalization of tumor vasculature with sunitinib resulted in objective response to cytotoxic chemotherapy. Chemotherapy treated PPARγ null mammary tumors exhibited luminal phenotype and expansion of unipotent CD61+ luminal progenitor cells. Transplantation of chemotherapy treated luminal progenitor cells recapitulated the luminal phenotype. These results have important implications for anti-angiogenic therapy in breast cancer patients. Citation Format: Crowe D, Kramer K, Wu J. Tumor suppressor control of the cancer stem cell angiogenic niche [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-09-01.