Purpose: A role for estrogens in determining lung cancer risk and prognosis is suggested by reported sex differences in susceptibility and survival. Archival lung tissue was evaluated for the presence of nuclear estrogen receptor (ER)-α and ER-β and the relationship between ER status, subject characteristics, and survival.

Experimental Design: Paraffin-embedded lung tumor samples were obtained from 214 women and 64 men from two population-based, case-control studies as were 10 normal lung autopsy samples from patients without cancer. Nuclear ER-α and ER-β expression was determined by immunohistochemistry. Logistic regression was used to identify factors associated with ER positivity and Cox proportional hazards models were used to measure survival differences by ER status.

Results: Neither tumor (0 of 94) nor normal (0 of 10) lung tissue stained positive for ER-α. Nuclear ER-β positivity was present in 61% of tumor tissue samples (170 of 278; 70.3% in men and 58.3% in women) and 20% of normal tissue samples (2 of 10; P = 0.01). In multivariate analyses, females were 46% less likely to have ER-β–positive tumors than males (odds ratio, 0.54; 95% confidence interval, 0.27-1.08). This relationship was stronger and statistically significant in adenocarcinomas (odds ratio, 0.40; 95% confidence interval, 0.18-0.89). Women with ER-β–positive tumors had a nonsignificant 73% (P = 0.1) increase in mortality, whereas men with ER-β–positive tumors had a significant 55% (P = 0.04) reduction in mortality compared with those with ER-β–negative tumors.

Conclusions: This study suggests differential expression by sex and influence on survival in men of nuclear ER-β in lung cancer, particularly in adenocarcinomas.