Role of Ras in Regulating mTORC2 Activity and Function in Breast Cancer Cell Migration

Abstract

The mechanistic Target of Rapamycin Complex 2 (mTORC2) is an evolutionarily conserved regulator of actin cytoskeleton dynamics. Although mTORC2 is an important promoter of cell migration, little has been learned about how mTORC2 is regulated. Beginning with Dictyostelium, an experimental model for studying cell migration, we found that the small GTPase RasC activates mTORC2 in Dictyostelium. Interestingly, Ras is the most common oncogene in human cancer and its oncogenic transformation is invariably linked to invasive and aggressive cancers. Our goal was to investigate the conservation of the Ras-mTORC2 pathway in humans and its potential role in cancer cell migration. Increasing evidence suggest mTORC2 is an important promoter of breast cancer cell migration. Ras is frequently upregulated in aggressive breast cancer due to the overexpression of either epidermal growth factor receptor (EGFR) or human EGF receptor 2 (HER2). The initial findings in human cells reported here, suggest that Ras proteins promote mTORC2 activation, including downstream of growth factor receptor signaling. Using prototypical cell lines representing different types of breast cancer, we found that mTORC2 controls breast cancer cell migration independently of breast cancer subtype. In addition, we observed that mTORC2 activity positively correlates with the level of Ras activity in the breast cancer cells. Using mammary epithelial MCF10A cells, we found that stimulation of HER2 led to a Ras-dependent increase in mTORC2 activity. Lastly, we found that mTORC2 was required for Ras-promoted cell migration and breast acini invasion. Together, our data suggest that the Ras-mediated activation of mTORC2 is conserved in human cells and may be a major pathway contributing to cell migration and invasion in breast cancer. Future studies will aim to identify the mechanism through which Ras activates mTORC2 and further describe the role of this pathway in promoting breast cancer cell migration and invasion.