The role of estrogen receptor alpha in lung cancer development and growth, a novel therapeutic target

4^th World Congress on Cancer Science & Therapy

October 20-22, 2014 DoubleTree by Hilton Hotel Chicago-North Shore Conference Center, USA

George G Chen, Ming-Yue Li, Angel W Y Kong, Yi Liu and Malcolm J Underwood

Accepted Abstracts: J Cancer Sci Ther

Abstract :

Lung cancer is the leading cause of cancer death. The treatment is very limited for the advantaged lung cancer and this is partly due to our poor understanding of lung carcinogenesis and the lack of effective treatment targets. Estrogen receptor alpha (ERa) plays a role in lung biology and pathology. Smoking carcinogen N-nitrosamines such as NNK is catalyzed by cytochrome P450 (CYP) family before they can promote lung cancer development and growth. However, the association between both ERa and CYP is unknown in smoking-induced lung tumorigenesis. In this study, CYP1B1, ERa and ERb were analyzed in the lung tumor mouse model and human lung cancer tissues and their roles in lung tumor development and growth were explored using various cellular and molecular approaches. Our in vivo study demonstrated that CYP1B1, ERa and ERb were over-expressed at the early stage of NNK-induced lung tumorigenesis. Microarray analysis found that ERa was involved in the ERK/MAPK Pathway. NNK activated RAS/ERK/AP1 as it remarkably increased the levels of p-ERK, c-Fos and c-Jun, but inhibited multiple negative regulators of Ras/ERK/AP1, pdcd4, spry1, spry2 and Btg2 through up-regulating miR- 21. Both CYP1B1 siRNA and ERK specific inhibitor suppressed NNK-mediated ERb up-regulation, suggesting that ERa is down-stream of CYP1B1and ERK. ERK inactivation led to the accumulation of CYP1B1, indicating that CYP1B1 is up-stream of ERK activation. Inhibition of ERK or ERa decreased NNK-induced cell proliferation, and block of CYP1B1 or ERa induced apoptosis in lung cancer cells. Therefore, we can conclude that ERa up-regulated by smoking carcinogen NNK contributes to the lung carcinogenesis. NNK-mediated ERa induction is via CYP1B1 and ERK activation. The inhibition of CYP1B1 or ERa may arrest the lung cancer cell proliferation and growth, indicating that they are likely to be novel therapeutic targets against smoking-related lung cancer.