Abstract

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 β (ERβ1) 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 ERβ1 reduced proliferation and enhanced apoptosis in the context of mutant RAS. ERβ1 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 ERβ1-induced apoptosis. Manipulation of EGFR and RAS expression and activity in ERβ1-expressing cells revealed the central role of oncogenic RAS inhibition in the ERβ1-mediated proapoptotic phenotype and EGFR regulation. These results demonstrate that ERβ1 decreases the survival of NSCLC cells by regulating oncogenic RAS signaling. The ability of ERβ1 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.

Highlights

  • Lung cancer is the leading cause of cancer-related death in both men and women worldwide

  • We hypothesized that ERb1 regulates cell survival in non–small cell lung cancer (NSCLC) and that high expression of ERb1 in NSCLC cells is associated with decreased cell proliferation and induction of apoptosis

  • The effect of ERb1 was more potent in H1299 and A549 cells that express mutant RAS compared with H661 cells that carry wild-type RAS, suggesting that ERb1 may suppress the growth of NSCLC cells by targeting oncogenic RAS signaling (Fig. 1A)

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Summary

Introduction

Lung cancer is the leading cause of cancer-related death in both men and women worldwide. Observations from population-based clinical studies propose a role for female steroid hormones in lung tumor development and progression. The nonsmoking related lung cancer is more common in women, and premenopausal women develop less differentiated lung cancer compared with postmenopausal women that have lower levels of circulating estrogen [2, 3]. Local production of estradiol has been observed in non–small cell lung cancer (NSCLC). Its concentration is higher in cancer tissues compared with nonneoplastic lung tissues and its intratumoral concentration has been associated positively with aromatase expression and markers of tumor growth in a group of male and postmenopausal female patients with NSCLC [4].

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