Tumor Suppressor Regulation of the Cancer Stem Cell Niche

Mammary stem cells (MSC) expansion is associated with aggressive human breast cancer. Tumorigenic MSC expansion is correlated with increased angiogenesis and poor clinical prognosis in human breast cancer. The mammary tumor suppressor peroxisome proliferator activated receptor γ (PPARγ) was previously shown to have anti-angiogenic effects, but the mechanisms for these observations were not completely characterized. Recently, anti-angiogenic therapy failed to extend patient survival in cancer clinical trials. To better understand these results, we genetically deleted expression of PPARγ in the mammary epithelium of a tumor prone in vivo model. Loss of PPARγ expression reduced tumor latency, expanded the CD24+/CD49fhi MSC population, and increased tumor cell proliferation. PPARγ null mammary tumors exhibited a dramatic angiogenic phenotype which also was detected in human breast cancer. In vivo genetic inhibition of a miR-15a/angiopoietin-1 pathway blocked not only increased angiogenesis but also MSC expansion and cell proliferation. PPARγ activated a response element in the 5’ flanking region of the miR-15a gene. PPARγ null mammary tumors were resistant to targeted anti-angiogenic or cytotoxic chemotherapy. However, normalization of tumor vasculature resulted in an objective response to cytotoxic chemotherapy. Chemotherapy treated PPARγ null mammary tumors exhibited dramatic expansion of unipotent CD61+ luminal progenitor cells which gave rise to luminal adenocarcinomas. These results have important implications for case selection and clinical response to anti-angiogenic therapy in breast cancer patients.