ER beta Regulates NSCLC Phenotypes by Controlling Oncogenic RAS Signaling

作者：Nikolos Fotis; Thomas Christoforos^*; Rajapaksa Gayani; Bado Igor; Gustafsson Jan Ake

来源：Molecular Cancer Research, 2014, 12(6): 843-854.

DOI：10.1158/1541-7786.MCR-13-0663

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 beta (ER beta 1) 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 ER beta 1 reduced proliferation and enhanced apoptosis in the context of mutant RAS. ER beta 1 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 ER beta 1-induced apoptosis. Manipulation of EGFR and RAS expression and activity in ER beta 1-expressing cells revealed the central role of oncogenic RAS inhibition in the ER beta 1-mediated proapoptotic phenotype and EGFR regulation. These results demonstrate that ER beta 1 decreases the survival of NSCLC cells by regulating oncogenic RAS signaling.

• 出版日期2014-6