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AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells

Oncogene volume 33, pages 1316–1324 (2014)Cite this article

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Abstract

Despite significant progress in the treatment of breast cancer, particularly through the use of targeted therapy, relapse and chemoresistance remain a major hindrance to the fight to minimize the burden of the disease. It is becoming increasingly clear that a rare subpopulation of cells known as cancer stem cells (CSC), able to be generated through epithelial-to-mesenchymal transition (EMT) and capable of tumor initiation and self-renewal, contributes to treatment resistance and metastases. This means that a more effective therapy should target both the chemoresistant CSCs and the proliferating epithelial cells that give rise to them to reverse EMT and to attenuate their conversion to CSCs. Here, we demonstrate a novel function of AXL in acting upstream to induce EMT in normal and immortalized human mammary epithelial cells in an apparent positive feedback loop mechanism and regulate breast CSC (BCSC) self-renewal and chemoresistance. Downregulation of AXL using MP470 (Amuvatinib) reversed EMT in mesenchymal normal human mammary epithelial cells and murine BCSCs attenuating self-renewal and restored chemosensitivity of the BCSCs. AXL expression was also found to be associated with the expression of stem cell genes, regulation of metastases genes, increased tumorigenicity and was important for BCSC invasion and migration. Inactivation of AXL also led to the downregulation of nuclear factor-κB pathway and reduced tumor formation in vivo. Taken together, our data suggest that targeted therapy against AXL, in combination with systemic therapies, has the potential to improve response to anticancer therapies and to reduce breast cancer recurrence and metastases.

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Acknowledgements

This work was supported by a generous gift from Martha and Bruce Atwater (KLK); Howard Temin Award, K01-CA100764 (KLK); R01-CA122086 (DCR); and the Mayo Clinic Breast Cancer Specialized Program of Research Excellence Award, P50-CA116201 (JNI). This publication was also supported by NIH/NCRR CTSA Grant Number UL1 RR024150. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. We acknowledge the strong support of the Mayo Clinic Comprehensive Cancer Center for providing access to core facilities.

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  1. M K Asiedu

    Present address: 4Current address: Department of Surgery, College of Medicine, Mayo Clinic, Rochester, MN, USA.,

Authors and Affiliations

  1. Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN, USA

    M K Asiedu, F D Beauchamp-Perez, M D Behrens & K L Knutson

  2. Department of Oncology, College of Medicine, Mayo Clinic, Rochester, MN, USA

    J N Ingle

  3. Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL, USA

    D C Radisky

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Correspondence to M K Asiedu or K L Knutson.

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Asiedu, M., Beauchamp-Perez, F., Ingle, J. et al. AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells. Oncogene 33, 1316–1324 (2014). https://doi.org/10.1038/onc.2013.57

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