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  • Original Article
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Tumor suppressor control of the cancer stem cell niche

Oncogene volume 35, pages 4165–4178 (2016)Cite this article

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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+/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.

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Acknowledgements

We thank Dr Ke Ma and Jewell Graves (University of Illinois Research Resources Center) for assistance with microscopy and flow cytometry. KK was supported by NIH National Research Service award DE18381. This study was supported by Department of Defense Breast Cancer Research Program award W81XWH-10-1-0081.

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  1. Cancer Center, University of Illinois, Chicago, IL, USA

    K Kramer, J Wu & D L Crowe

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  1. K Kramer
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  2. J Wu
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  3. D L Crowe
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Correspondence to D L Crowe.

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Kramer, K., Wu, J. & Crowe, D. Tumor suppressor control of the cancer stem cell niche. Oncogene 35, 4165–4178 (2016). https://doi.org/10.1038/onc.2015.475

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