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Published on: May 11, 2016
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 γ (PPARγ) is a breast cancer tumor suppressor, but the mechanisms of this suppression are not completely characterized. To determine whether 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+/CD49f(hi) 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.
Insights
Loss of peroxisome proliferator activated receptor γ (PPARγ) in breast cancer promotes aggressive tumors by expanding mammary stem cells (MSCs) and increasing angiogenesis. Targeting angiogenesis may improve chemotherapy response in these aggressive breast cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Mammary stem cell (MSC) expansion correlates with aggressive breast cancer.
- Peroxisome proliferator activated receptor γ (PPARγ) acts as a tumor suppressor in breast cancer, but its mechanisms are not fully understood.
Purpose of the Study:
- To investigate the role of PPARγ in regulating MSC expansion within mammary tumors.
- To elucidate the molecular mechanisms by which PPARγ suppresses breast cancer progression.
Main Methods:
- Deletion of PPARγ in the mammary epithelium of an in vivo basal breast cancer model.
- Analysis of tumor latency, MSC population (CD24+/CD49f(hi)), angiogenesis, and gene expression (miR-15a).
- In vivo inhibition of the miR-15a/angiopoietin-1 pathway and drug sensitivity testing (sunitinib, chemotherapy).
Main Results:
- Loss of PPARγ reduced tumor latency and expanded the MSC population.
- PPARγ-null tumors showed increased angiogenesis, mediated by a PPARγ-regulated miR-15a/angiopoietin-1 pathway.
- PPARγ-null tumors were sensitive to anti-angiogenic sunitinib but resistant to chemotherapy; sunitinib normalized vasculature and sensitized tumors to chemotherapy, leading to luminal progenitor cell expansion.
Conclusions:
- PPARγ suppresses aggressive breast cancer by inhibiting MSC expansion and angiogenesis.
- Targeting angiogenesis with sunitinib can overcome chemotherapy resistance in PPARγ-deficient breast tumors.
- These findings have significant implications for developing novel anti-angiogenic therapies for breast cancer patients.
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