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)-a and ER-h 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-a and ER-h 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-a. Nuclear ER-h 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-h^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 ERh^positive tumors had a nonsignificant 73% (P = 0.1) increase in mortality, whereas men with ER-h^positive tumors had a significant 55% (P = 0.04) reduction in mortality compared with those with ER-h^negative tumors. Conclusions: This study suggests differential expression by sex and influence on survival in men of nuclear ER-h in lung cancer, particularly in adenocarcinomas.In the United States, lung cancer is the second most common cancer among both men and women and is the leading cause of cancer death in both sexes (1). A number of studies report that women are more susceptible, dose for dose, to the carcinogenic effects of cigarette smoke than men (2, 3). Women have been reported to have higher levels of polycyclic aromatic hydrocarbon-DNA adducts than men at any given level of smoking (4). Smoking females have significantly higher levels of expression of the gene encoding CYP1A1, a central enzyme in the metabolic activation of polycyclic aromatic hydrocarbons (4, 5). It has also been shown that G:C to T:A transversions in p53 are more common among females with lung cancer than males (6). One study also reported that the proportion of nonsmoking lung cancer cases in women was double that in men, suggesting that even nonsmoking women may be more susceptible to lung carcinogens than nonsmoking men (2).The reported sex difference in susceptibility suggests a role for hormones in determining lung cancer risk. Both exogenous estrogens [i.e., hormone replacement therapy (HRT) and oral contraceptives] and endogenous hormone levels (i.e., age at menopause) may contribute to the development of lung cancer (7 -10). Early age at menopause has been associated with decreased risk of adenocarci...

Resistance to endocrine therapy is common among breast cancer patients with estrogen receptor alpha-positive (ER+) tumors and limits the success of this therapeutic strategy. While the mechanisms that regulate endocrine responsiveness and cell fate are not fully understood, interferon regulatory factor-1 (IRF1) is strongly implicated as a key regulatory node in the underlying signaling network. IRF1 is a tumor suppressor that mediates cell fate by facilitating apoptosis and can do so with or without functional p53. Expression of IRF1 is downregulated in endocrine-resistant breast cancer cells, protecting these cells from IRF1-induced inhibition of proliferation and/or induction of cell death. Nonetheless, when IRF1 expression is induced following IFNγ treatment, antiestrogen sensitivity is restored by a process that includes the inhibition of prosurvival BCL2 family members and caspase activation. These data suggest that a combination of endocrine therapy and compounds that effectively induce IRF1 expression may be useful for the treatment of many ER+ breast cancers. By understanding IRF1 signaling in the context of endocrine responsiveness, we may be able to develop novel therapeutic strategies and better predict how patients will respond to endocrine therapy.

Tamoxifen is well known for its actions as an antagonist of estrogen receptor-mediated signaling and is one of the most extensively used endocrine agents both in the clinic and in the research setting. Tamoxifen has emerged from recent Breast Cancer Prevention Trials, conducted to evaluate risk reduction, as an effective preventive agent. Specifically, comparing tamoxifen to placebo (for 5 years) has shown that tamoxifen: (a) significantly reduced the risk of breast cancer recurrence, in those with a history of the disease; (b) reduced or delayed breast cancer progression, from an noninvasive to invasive breast cancer; (c) prevented or substantially reduced the risk of getting breast cancer (risk of occurrence) in healthy women with risk factors. The extraordinary outcomes offer support for the use of tamoxifen in multilevel preventive approaches and predict that it will continue to be vital in facilitating mechanistic studies. Information produced by mechanistic studies is needed to understand how to prevent cancer and how to confront treatment problems such as resistance. Molecular determinants of the resistant phenotype to tamoxifen are currently being identified. The next major effort will be to link these determinants to readily detectable biological changes that could be used to indicate the development of resistance before clinical manifestations develop.

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