ERß regulates NSCLC phenotypes by controlling oncogenic RAS signaling.

ABSTRACT

UNLABELLED Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. In addition to the aberrant growth factor signaling, dysregulation of other pathways, such as those mediated by estrogens and their receptors, has been linked to NSCLC initiation and progression. Although the expression of wild-type estrogen receptor ß (ERß1) has been associated with prolonged disease-free survival in patients with NSCLC, the molecular mechanism that accounts for this correlation is unknown. Here, upregulation of ERß1 reduced proliferation and enhanced apoptosis in the context of mutant RAS. ERß1 was found to induce apoptosis by stimulating the intrinsic apoptotic pathway that involves BIM, a Bcl-2 proapoptotic family member that is regulated by the extracellular signal-regulated kinase (ERK). Downregulation of EGFR and inactivation of RAS and the downstream components ERK1/2 were found to be involved in the ERß1-induced apoptosis. Manipulation of EGFR and RAS expression and activity in ERß1-expressing cells revealed the central role of oncogenic RAS inhibition in the ERß1-mediated proapoptotic phenotype and EGFR regulation. These results demonstrate that ERß1 decreases the survival of NSCLC cells by regulating oncogenic RAS signaling. IMPLICATIONS The ability of ERß1 to regulate the oncogenic functions of RAS suggests its importance in the biology of NSCLC and its clinical management. Mol Cancer Res; 12(6); 843-54. ©2014 AACR.