Tumor suppressor control of the cancer stem cell niche.

ABSTRACT: Mammary stem cells (MSCs) expansion is associated with aggressive human breast cancer. The nuclear receptor peroxisome proliferator activated receptor ? (PPAR?) is a breast cancer tumor suppressor, but the mechanisms of this suppression are not completely characterized. To determine whether PPAR? regulates MSC expansion in mammary cancer, we deleted PPAR? expression in the mammary epithelium of an in vivo model of basal breast cancer. Loss of PPAR? expression reduced tumor latency, and expanded the CD24+/CD49f(hi) MSC population. PPAR?-null mammary tumors exhibited increased angiogenesis, which was detected in human breast cancer. In vivo inhibition of a PPAR?-regulated miR-15a/angiopoietin-1 pathway blocked increased angiogenesis and MSC expansion. PPAR? bound and activated a canonical response element in the miR-15a gene. PPAR?-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 PPAR?-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.

SUBMITTER: Kramer K 

PROVIDER: S-EPMC5859337 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature