Abstract LB-272: AXL induces epithelial to mesenchymal transition and regulates the function of breast cancer stem cells.

Abstract

Abstract Despite significant progress in the treatment of breast cancer particularly through the use of targeted therapy, relapse and chemo-resistance remain a major hindrance in the fight to minimize the burden of the disease. Accumulating evidence suggest that breast cancer stem cells (BCSCs), which show resistance to chemotherapy and radiation, drive tumor initiation and disease recurrence. 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 in order to reverse EMT and 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 expression using AXL inhibitor MP470 (amuvatinib) or shRNA 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 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 downregulation of NFκB pathway and reduced tumor formation in vivo. Together, our data suggest that targeted therapy against AXL, in combination with systemic therapies, has the potential to improve response to anti-cancer therapies and to reduce breast cancer recurrence and metastases. Citation Format: Michael K. Asiedu, Francis Beauchamp-Perez, James N. Ingle, Marshall D. Behrens, Derek C. Radisky, Keith Knutson. AXL induces epithelial to mesenchymal transition and regulates the function of breast cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-272. doi:10.1158/1538-7445.AM2013-LB-272