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Date of release: 20 December, 2010

Role of estrogens in lung cancer progression


The role of estrogens in lung cancer remains elusive. Estrogens stimulate growth in both normal and tumoral lung epithelial cells. Aromatase is active in normal lung tissue and lung cancer cells. Both isoforms of estradiol receptor (ER), alpha (ERα) and beta (ERβ), have been detected in lung cancer tissue and normal lung cells. The results of literature concerning the presence of ERα in lung tumors and normal lung cells remain insufficiently documented, with divergent results. In a recently published study [1], the authors aimed to investigate whether serum estrogen levels and tumor ERα, ERβ and progesterone receptor (PR) gene expressions were associated with lung cancer survival in three independent cohorts. In addition, they examined the role of single-nucleotide polymorphisms (SNPs) of genes involved in the estrogen biosynthesis pathway in lung cancer survival. The three cohorts studied were the case–case cohort, the case–control cohort, and the case-only cohort. The National Cancer Institute-Maryland (NCI-MD) case–case cohort recruited 100 postmenopausal women and 205 men with non-small-cell lung cancer. In addition to usual demographic data, smoking habits and passive smoking were recorded by interview. Serum samples were available from 191 (63%) of the cases (126 males and 65 females). The NCI-MD case–control cohort recruited 227 patients with lung cancer and information was obtained by interviews. The Norwegian case-only cohort recruited 282 lung cancer cases at the time of surgery for non-small-cell lung cancer between 1986 and 2007 and also interviews were obtained. Blood samples were obtained at the time of interviews in the three cohorts. 


 


The mean ages were identical between the three populations (65 years). Smoking status differed across the cohorts. Fifty-nine percent of the Norwegian cases were current smokers, whereas only 46% of the cases from the NCI-MD case–control cohort were current smokers. The main result was that higher levels of serum estrogen and poorer survival were very significantly correlated in the three studies. In addition, in the NCI-MD case–case cohort, lung cancers which were ERα mRNA-positive had worse survival than those which were tumor ERα mRNA-negative (hazard ratio (HR) 3.53, 95% confidence interval (CI) 1.17–10.62); however, this association was not significant in the Norwegian case-only cohort (HR 1.22, 95% CI 0.78–1.90). The association between estrogen levels and ER expression with poor prognosis was observed among both men and women. This association of tumor ERα expression with lung cancer survival was also more strongly observed among adenocarcinomas in the NCI-MD case–case cohort. Patients with ERβ-positive tumors had slightly shorter lung cancer survival than those that with ERβ-negative tumors in the NCI-MD case–case cohort (p for log-rank 0.04), but this was not significant in the Norwegian case-only cohort (p for log-rank 0.85). Several SNPs in the aromatase gene were associated with serum estrogen levels and with lung cancer survival in all three cohorts. The variant ESR1-07, a SNP in exon 8 of the ERα gene, was associated with tumor ERα mRNA expression levels and expression levels of tumor PR mRNA but not associated with serum estrogen levels; it was also significantly associated with poorer survival in all three cohorts. Higher levels of progesterone were associated with worse survival among men only in the NCI-MD case–case cohort but not in the other cohorts nor in women.

Comment

This paper gives some important information on the role of estrogens in lung cancer progression. The results suggest a strong link between prognosis of lung cancer and local production of estrogens and their local utilization. So far, the issue of the role of estrogens in lung cancer remains not well understood. Discrepancy in the results concerning both the presence of ERs and the role of estrogens can come from the fact that the histological type of lung cancer is not always described or taken into account. In addition, it is possible that the natural history and biology of lung cancers occurring in smokers and non-smokers are not equivalent [2]. Adenocarcinomas are more frequent in women than in men and less associated with smoking [2]. The prognosis of lung cancer seems also to depend on age: lung cancer is reported to be more aggressive in women than men before menopause and less after [2]. Most of the studies have not found any ERα in the tumors of lung cancer or, when found, it was only in the cytoplasm of the tumoral cells. However, a recent study has shown that ERα nuclear expression significantly correlated with adenocarcinoma histology, female gender, and history of never smoking [3]. In the study from Olivo-Marston and colleagues [1], only the level of expression of ERα was studied. 
 
The role of endogenous and exogenous estrogens on lung cancer incidence is not clear. For example, parity has been shown to increase the risk in some studies and to decrease it in others. The Nurses’ Health Study has shown that parity decreased the risk in non-smokers and increased it in smokers. In this study, hormone replacement therapy (HRT) did not influence lung cancer risk. Some studies have shown a worse prognosis in women under HRT such as the Women’s Health Initiative [4], whereas others reported a decrease in the risk in women using HRT. Several case–control studies [5-8] reported a decrease in the incidence of lung cancer in women under HRT (estrogen alone or combined therapy), with an increase in the protective effect with time [5] and also a decrease under oral contraception but only in smokers [5]. Similarly, the protective effect under HRT in some studies was only apparent in smokers [5,8]. Thus, the protective effect of estrogen on lung incidence could be particularly important in smokers. Otherwise, HRT could be increasing aggressivity only in tumors bearing ERs, as reported in this paper [1]. It seems likely that it could be dependent on the presence or absence of ERs. It was actually shown that there was a link between ER, EGFR and prognosis, mostly in adenocarcinoma [3]. 
 
Furthermore, in the paper from Raso and colleagues [3], the nuclear localization of ERα was found only in adenocarcinoma. In addition, smoking is known to decrease the availability of estrogens. It is possible that estrogens and smoking interact or that estrogens act differently in lung cancer arising in smokers. Thus, a beneficial effect of estrogens could be related at least partially to the histology or to the prevalence of smoking. However, more work is needed to clarify the complex relationship between hormones and lung cancer.

Comentario

Anne Gompel
Unité de Gynécologie-Endocrinienne, APHP, Hôtel-Dieu Hospital and University Paris Descartes, France

    References

  1. Olivo-Marston SE, Mechanic LE, Mollerup S, et al. Serum estrogen and tumor-positive estrogen receptor-alpha are strong prognostic classifiers of non-small-cell lung cancer survival in both men and women. Carcinogenesis 2010;31:1778-86.
    http://www.ncbi.nlm.nih.gov/pubmed/20729390

  2. Egleston BL, Meireles SI, Flieder DB, Clapper ML. Population-based trends in lung cancer incidence in women. Semin Oncol 2009;36:506-15.
    http://www.ncbi.nlm.nih.gov/pubmed/19995642

  3. Raso MG, Behrens C, Herynk MH, et al. Immunohistochemical expression of estrogen and progesterone receptors identifies a subset of NSCLCs and correlates with EGFR mutation. Clin Cancer Res 2009;15:5359-68.
    http://www.ncbi.nlm.nih.gov/pubmed/19706809

  4. Chlebowski RT, Schwartz AG, Wakelee H. Oestrogen plus progestin and lung cancer in postmenopausal women (Womens Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet 2009;374:1243-51.
    http://www.ncbi.nlm.nih.gov/pubmed/19767090

  5. Kreuzer M, Gerken M, Heinrich J, Kreienbrock L, Wichmann HE. Hormonal factors and risk of lung cancer among women? Int J Epidemiol 2003;32:263-71.
    http://www.ncbi.nlm.nih.gov/pubmed/12714547

  6. Schabath MB, Wu X, Vassilopoulou-Sellin R, et al. Hormone replacement therapy and lung cancer risk: a case-control analysis. Clin Cancer Res 2004;10:113-23.
    http://www.ncbi.nlm.nih.gov/pubmed/14734459

  7. Chen KY, Hsiao CF, Chang GC. Hormone replacement therapy and lung cancer risk in Chinese. Cancer 2007;110:1768-75.
    http://www.ncbi.nlm.nih.gov/pubmed/17879370

  8. Ramnath N, Menezes RJ, Loewen G, et al. Hormone replacement therapy as a risk factor for non-small cell lung cancer: Results of a case-control study. Oncology 2007;73:305-10.
    http://www.ncbi.nlm.nih.gov/pubmed/18493157