Mechanistic insight into sex differences in lung cancer induced by cRaf

Women are at greater risk of developing lung cancer (LC); yet the underlying causes are unknown. To gain insight into sex difference in LC, we investigated tumor growth in a cRaf transgenic disease model. Overexpression of the cRaf kinase induced an extraordinary 8-fold increase in tumor growth among females, and nearly 70% of the 112 differentially expressed genes (DEGs) were female specific. We identified oncogenes, oncomirs, tumor suppressors, cell cycle regulators and MAPK/EGFR signaling molecules, which prompted sex-based differences in LC, and we report a regulatory gene-network, which protected males from accelerated tumor growth. Strikingly, 41% of DEGs are targets of hormone receptors, and the majority (85%) are estrogen receptor (ER) dependent. We confirmed the role of ER in a large cohort of LC patients and validated 40% of DEGs induced by cRaf in clinical tumor samples. Together, we report a molecular circuitry that prompted gender disparities in tumor growth, and propose the development of molecular targeted therapies by jointly blocking ER, CDK1 and arginase 2 activity in LC.