hTERT enables heterogeneity in a population of HMEC which sustains oncogene sensitive and resistant clones

Abstract

Mammalian cells activate multiple mechanisms of defense against uncontrolled proliferation when oncogenic mutations occur. In this way, the process of transformation relies on breaching such defenses to promote cancer. Telomere maintenance, mediated by expression of telomerase in cancer cells, is associated with evasion of proliferative senescence, a known barrier against cancer. Whether telomerase contributes to deregulate activation of other mechanisms of defense is not clear in the field. We decided to study whether expression of telomerase deregulates the activation of known mechanisms of defense by comparing primary Human Mammary Epithelial cells (HMECS) and hTERT immortalized HMECS when they express oncogenic Ras. To our surprise we found that contrary to primary cells, hTERT immortalized cells respond differently against oncogenic Ras by undergoing post-replication arrest and destructive autophagy. Although these barriers were available, the population of cells did not respond uniformly against oncogenic Ras. Instead, we observed variability in the execution of these responses. Our results suggest that the process of immortalization fosters the opportunity for evolution of the population. In these conditions many cells can harness mechanisms of defense while a minority of cells becomes resistant to them, an important characteristic for further cancer progression.