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Expression of miR-200c in claudin-low breast cancer alters stem cell functionality, enhances chemosensitivity and reduces metastatic potential

Oncogene volume 34, pages 5997–6006 (2015)Cite this article

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Abstract

Claudin-low tumors are a highly aggressive breast cancer subtype with no targeted treatments and a clinically documented resistance to chemotherapy. They are significantly enriched in cancer stem cells (CSCs), which makes claudin-low tumor models particularly attractive for studying CSC behavior and developing novel approaches to minimize CSC therapy resistance. One proposed mechanism by which CSCs arise is via an epithelial–mesenchymal transition (EMT), and reversal of this process may provide a potential therapeutic approach for increasing tumor chemosensitivity. Therefore, we investigated the role of known EMT regulators, miR-200 family of microRNAs in controlling the epithelial state, stem-like properties and therapeutic response in an in vivo primary, syngeneic p53null claudin-low tumor model that is normally deficient in miR-200 expression. Using an inducible lentiviral approach, we expressed the miR-200c cluster in this model and found that it changed the epithelial state, and consequently, impeded CSC behavior in these mesenchymal tumors. Moreover, these state changes were accompanied by a decrease in proliferation and an increase in the differentiation status. miR-200c expression also forced a significant reorganization of tumor architecture, affecting important cellular processes involved in cell–cell contact, cell adhesion and motility. Accordingly, induced miR200c expression significantly enhanced the chemosensitivity and decreased the metastatic potential of this p53null claudin-low tumor model. Collectively, our data suggest that miR-200c expression in claudin-low tumors offers a potential therapeutic application to disrupt the EMT program on multiple fronts in this mesenchymal tumor subtype, by altering tumor growth, chemosensitivity and metastatic potential in vivo.

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Acknowledgements

These studies were supported by grants CA148761 (JMR and CP) from the National Cancer Institute and RP130485 (JMR) and RP140102 (JK) from CPRIT. This project was supported by the following core facilities and their funding: Biostatistics and Informatics (P30-CA125123) and Cytometry and Cell Sorting Core at Baylor College of Medicine (P30 AI036211, P30 CA125123 and S10 RR024574). RPPA arrays were performed at the MD Anderson Cancer Center RPPA Core Facility–Functional Proteomics. We thank Drs Kevin Roarty Amy Shore and Michael Toneff for helpful discussions and paper editing, Dr Jason Herschkowitz for help and advice, and Ms Shirley Small for animal husbandry.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    J Knezevic, I Petrovic & J M Rosen

  2. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA

    A D Pfefferle & C M Perou

  3. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    A D Pfefferle & C M Perou

  4. Epic Sciences, Inc., San Diego, CA, USA

    S B Greene

  5. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    C M Perou

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  1. J Knezevic
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Correspondence to J M Rosen.

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Knezevic, J., Pfefferle, A., Petrovic, I. et al. Expression of miR-200c in claudin-low breast cancer alters stem cell functionality, enhances chemosensitivity and reduces metastatic potential. Oncogene 34, 5997–6006 (2015). https://doi.org/10.1038/onc.2015.48

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