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Reproductive Factors, Hormone Use, Estrogen Receptor Expression and Risk of Non–Small-Cell Lung Cancer in Women

Ann G. Schwartz, Angela S. Wenzlaff, Geoffrey M. Prysak, Valerie Murphy, Michele L. Cote, Sam C. Brooks, Debra F. Skafar, Fulvio Lonardo

From the Population Studies and Prevention Program, Breast Cancer Program, and Developmental Therapeutics Program, Karmanos Cancer Institute; Departments of Internal Medicine, Biochemistry and Molecular Biology, Physiology, and Pathology, Wayne State University School of Medicine, Detroit, MI

Address reprint requests to Ann G. Schwartz, PhD, MPH, Karmanos Cancer Institute, 110 E Warren Ave, Detroit, MI 48201; e-mail: schwarta{at}karmanos.org

	ABSTRACT

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Purpose Estrogen receptor (ER) expression in lung tumors suggests that estrogens may play a role in the development of lung cancer. We evaluated the role of hormone-related factors in determining risk of non–small-cell lung cancer (NSCLC) in women. We also evaluated whether risk factors were differentially associated with cytoplasmic ER- and/or nuclear ER-β expression–defined NSCLC in postmenopausal women.

Patients and Methods Population-based participants included women aged 18 to 74 years diagnosed with NSCLC in metropolitan Detroit between November 1, 2001 and October 31, 2005. Population-based controls were identified through random digit dialing, matched to patient cases on race and 5-year age group. Interview data were analyzed for 488 patient cases (241 with tumor ER results) and 498 controls.

Results Increased duration of hormone replacement therapy (HRT) use in quartiles was associated with decreased risk of NSCLC in postmenopausal women (odds ratio = 0.88; 95% CI, 0.78 to 1.00; P = .04), adjusting for age, race, pack-years, education, family history of lung cancer, current body mass index, years exposed to second-hand smoke in the workplace, and obstructive lung disease history. Among postmenopausal women, ever using HRT, increasing HRT duration of use in quartiles, and increasing quartiles of estrogen use were significant predictors of reduced risk of NSCLC characterized as ER- and/or ER-β positive. None of the hormone-related variables were associated with nuclear ER-–or ER-β–negative NSCLC.

Conclusion These findings suggest that postmenopausal hormone exposures are associated with reduced risk of ER-–and ER-β–expressing NSCLC. Understanding tumor characteristics may direct development of targeted treatment for this disease.

	INTRODUCTION

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Lung cancer in women has several different characteristics than lung cancer in men, with women more likely to have adenocarcinomas of the lung, higher risk in never smokers,¹ higher levels of polycyclic aromatic hydrocarbon-DNA adducts at any given level of smoking,² higher levels of expression of the gene encoding CYP1A1,^2,3 more frequent G:C to T:A transversions in p53,⁴ and more frequent epidermal growth factor receptor mutations⁵ than men. These findings led to investigation into the role of estrogens in determining lung cancer risk. Epidemiologic evidence supporting a role for reproductive and estrogen use history in lung cancer development has been somewhat inconsistent, with reports of increased risk of adenocarcinomas with use of estrogen replacement therapy^6,7, as well as reduced risk with use of oral contraceptives (OC) and hormone replacement therapy (HRT).^8-10

Research focused on the role of estrogens and lung cancer has extended into investigations of estrogen receptors (ER). Two subtypes of the ER have been described, ER- and ER-β, both of which have a high affinity for estradiol. Several studies suggest frequent expression of ER in lung tumors.^11-15 Nuclear ER-β is present in the normal lung^16-18 and is abundant in lung tumor tissue.^15,19 There is less consensus on the occurrence of ER- in the lung, although it seems that the ER- in the lung may be present in a fragmented, non-nuclear form.¹⁵

Given the potential for estrogen to interact with ERs in the lung and its effect on cell growth, we evaluated the role of reproductive factors and hormone use in determining risk of non–small-cell lung cancer (NSCLC) in women in a large population-based study. We further studied these risk factors for their association with cytoplasmic ER-–and nuclear ER-β–defined NSCLC with the hypothesis that estrogen use affects risk differentially for ER-positive and ER-negative tumors.

	PATIENTS AND METHODS

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Study Participants
Patients were enrolled through the population-based Metropolitan Detroit Cancer Surveillance System, a participant in the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Women aged 18 to 74 years diagnosed with primary NSCLC in Wayne, Macomb, and Oakland counties between November 1, 2001 and October 31, 2005 were eligible to participate. Ascertainment was originally focused on adenocarcinoma histology but was broadened after November 1, 2004 to include all NSCLC histologic types because many histologic diagnoses at the time of rapid participant ascertainment were not more specific. Seventy-one percent of patients had adenocarcinoma histology, 8% had squamous cell carcinoma, 3% had large-cell carcinoma, and 17% had NSCLC unspecified, reflecting this sampling method.

Five hundred eighty-five women (54%) completed an in-person interview. The highly fatal nature of lung cancer and the likelihood of a late-stage diagnosis meant that many women were too ill (n = 135) to participate. We could not locate a working phone number for another 89 women, and 270 women refused. Women self-reporting race other than African American or white (n = 16) and women with an unknown menstrual status (n = 26) were excluded. Fifty-five patients with a previous history of breast cancer were excluded because of the associations between reproductive factors and breast cancer risk, thus ensuring that associations detected were not driven by differences in breast cancer risk factors between patient cases and controls. In total, 488 women were available for analysis.

Population-based controls were identified through random digit dialing. Control women were frequency matched to patient cases on race and 5-year age group. Of the households willing to complete the brief eligibility screening questionnaire, 70.6% (n = 538) participated. Twenty-two controls reporting a previous breast cancer diagnosis, 11 reporting race other than African American or white, and seven with unknown menstrual status were excluded, leaving 498 controls for analysis.

Data and Biospecimen Collection
All local institutional and review boards approved this study. Informed consent was obtained from each participant before study participation. In-person interviews were conducted to collect demographic information, smoking history, health history, reproductive history, and environmental tobacco smoke exposure. Medical history included self-report of physician diagnoses of asthma, emphysema, allergies, pneumonia, bronchitis, chronic obstructive pulmonary disease, tuberculosis, and cancer. Emphysema, chronic obstructive pulmonary disease, and chronic bronchitis were combined to create a broad chronic obstructive lung disease variable. Diagnoses reported within 1 year of lung cancer diagnosis (for patient cases) or interview (for the controls) were excluded. Reproductive data collected included age menses began and ended, menstrual cycle length, number of pregnancies, and number of children born. Dates and dosages for OC use and HRT were collected. Estrogen only, estrogen combined with progesterone, progesterone only, and unknown HRT formulations were included as HRT use in analyses. Duration of OC and HRT use was categorized in quartiles based on use among the controls. Detailed dose data for women taking HRT were available for 51.1% of patient cases and 50.6% of controls. A cumulative lifetime estrogen exposure measure, calculated by multiplying dose by months of use and summing over the lifetime (mg x months), was analyzed in quartiles based on data from controls. Family history of lung cancer was coded as yes or no based on the detailed first-degree family history information.

Immunohistochemistry
Lung tumor samples from women who had undergone surgical treatment were available for 241 patients. The methods for evaluating nuclear ER-β expression have been discussed previously.¹⁹ Five-micron sections of lung tumor tissue were stained using the antibody ER-β-MCA1974S (Serotec, Oxford, United Kingdom), which is raised against the C terminus of the β1 isoform of ER-β. Positive controls for ER-β included benign hyperplastic prostate tissue, breast tissue, and granulosa cell carcinoma of the ovary. Fragmented, cytoplasmic ER- was assayed using an antibody to the C terminus (Santa Cruz sc-543; Santa Cruz Biotechnology, Santa Cruz, CA). Breast cancer tissue served as a positive control for ER-. Results for ER- and ER-β were each scored separately for intensity and extent of positivity. Intensity was scored in an ascending 1 to 3 scale. Extent of positivity was defined by the percentage of positive tumor cells in the sample, as follows: 1 for 10%, 2 for 11% to 49%, and 3 for 50%. Positive results were measured conservatively as samples with at least weak (1+) staining in 10% of tumor cells. The pathologist was blinded to all patient characteristics.

Statistical Analysis
Comparisons of dichotomous risk factors were made between patient cases and controls using ² tests; comparisons of means were conducted using Student's t tests. Multivariate unconditional logistic regression models were used to estimate odds ratios (ORs) and 95% CI. Initial models were based on nonreproductive and nonhormone-related factors to identify a set of independent, significant (P < .05) risk factors to be included in all subsequent models. These factors included age (continuous variable), race, education, pack-years of smoking (continuous variable), history of chronic obstructive lung disease, current body mass index (continuous variable), years exposed to passive smoke in the workplace (continuous variable), and family history of lung cancer. Each reproductive and hormone-related variable was introduced individually into this model to test for statistical significance. Stepwise logistic models were then created using all reproductive and hormone-related variables that were significant at P < .1 in the previous models described. Any factor with a P < .1 was retained in the model. These models were also used to test for associations between risk factors and NSCLC development defined by ER- and ER-β expression. Stratified analyses were used to evaluate the effects of race, age at diagnosis, histologic type, HRT type, and smoking history. All statistical analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC).

	RESULTS

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Patient cases and controls differed in age (1.7 years), ever smoking, mean pack-years among smokers, years of environmental tobacco smoke exposure, education, body mass index at the time of interview, personal history of chronic obstructive lung disease, and first-degree family history of lung cancer (Table 1).

View this table: [in this window] [in a new window]   Table 6. Risk Estimates for Developing NSCLC Among Postmenopausal Women by Tumor ER- Expression and ER-β Expression

	DISCUSSION

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We show a significant decrease in NSCLC risk among HRT users, with evidence of a duration-dependent effect, for cytoplasmic ER-–and/or nuclear ER-β–positive NSCLC. Sixty-six percent and 49% of our lung tumors stained positive for cytoplasmic ER- and nuclear ER-β, respectively. These percentages are consistent with other studies.^19-22 Several studies have shown increased ER- and ER-β expression in lung tumor tissue versus adjacent normal tissue,^19-21,23 with the same localization pattern reported here.¹⁵ To our knowledge, this is the only study with enough patient cases and collection of reproductive and hormone use data to evaluate lung cancer risk associated with exogenous estrogen use by ER tumor expression.

Both nuclear and cytoplasmic localization of ER- and ER-β have been reported.²⁴ Estrogens and ERs play important roles in regulating growth and differentiation of various tissues by acting through at least two different ligand-activated mechanisms. One mechanism involves binding of a ligand to ER nuclear receptors, altering transcription by binding to the estrogen-response element or to transcription factors in the promoter regions of target genes.^25,26 Nuclear ER-, in the presence of estrogen, activates transcription at AP-1 sites, whereas nuclear ER-β bound to estrogen results in inhibition of transcription.²⁷ The finding of decreased risk of tumors expressing nuclear ER-β with HRT use fits in this pathway (ie, use of HRT is associated with increased levels of estrogen, which binds to ER-β in the lung, reducing transcription and thus reducing cell growth). However, estrogen action in the lung is not likely to be explained so simply. Dose and duration of HRT use is only an indirect measure of lung tissue exposure to estrogen. Actual estrogen level in lung tissue, both from endogenous and exogenous estrogens, was not measured.

The role of cytoplasmic ER- is less clear.²⁴ Hershberger et al²² suggest that cytoplasmic ER- is unlikely to be a transcriptional mediator in response to estrogen in NSCLC. However, Stabile et al¹⁵ showed that estrogen stimulates transcription 1.5- to two-fold in lung cancer cell lines expressing cytoplasmic ER- and nuclear ER-β.

Alternative pathways of estrogen action in the lung have been demonstrated. In NSCLC cell lines, estradiol promotes an association between ER-β and GRIP1/TIF2 coactivators that modifies gene expression²² and stimulates cell growth.^22,28 E-cadherin and Id-2 levels increase, whereas antiestrogen treatment using faslodex (ICI 182780) decreased expression of these proteins when ER-β–expressing cell lines were treated with estradiol. These data suggest that lung cells respond to estrogen and estrogen alters growth.

A potential second mechanism of action involves cross-talk between ERs and growth factor receptor–mediated pathways in the plasma membrane.²⁹ Yu et al³⁰ found that estradiol and tamoxifen citrate stimulate genomic events (through increased expression of c-myc) and nongenomic events (through rapid cytoplasmic activation of p44/42 mitogen-activated protein kinase) via ER- and ER-β mechanisms in pulmonary lymphangioleiomyomatosis cells. Epidermal growth factor receptor protein is downregulated in response to estrogen and upregulated by antiestrogens in these same cell lines.³¹

Estrogen and ER mRNA and protein expression in normal lung and lung tumor tissue may also affect mRNA expression in the lung of phase I and phase II enzymes involved in metabolism of tobacco smoke carcinogens. In nontumor lung tissue, ER-β expression has been positively correlated with CYP1B1 expression (P = .024) and NQO1 expression (P = .001) in women and positively correlated with GSTT1 expression in men (P = .025).³² In lung tumor tissue, ER-β expression was negatively correlated with GSTT1 expression in women (P = .005), and ER- expression was positively correlated with NQO1 expression in men (P = .001). In the same case series (n = 45), plasma estradiol was positively correlated with GSTT1 expression in men (P = .015). Given that multiple pathways of estrogen action exist, much additional work is needed to determine mechanisms of action of estrogen in the lung.

The current study uses a large population-based sample but has some limitations. HRT use is based on individual recollection, but the potential for recall bias should be minimal because HRT use among postmenopausal women is primarily current or recent. Recall bias may be greater for OC use, but recall is unlikely to occur differentially for patients and controls. Recall bias was also minimized by the use of a calendar to record significant events in a woman's life. Another potential limitation is the somewhat low response rate for interview and tumor retrieval common to most population-based lung cancer studies because of the high patient fatality rate and limited surgical intervention. Therefore, study results may only be applicable to a subset of all women with NSCLC and most specifically to adenocarcinomas. Nevertheless, to our knowledge, this is the first study to demonstrate associations between hormone use and lung cancer risk that vary by tumor ER expression.

Overall, we have shown an inverse relationship between HRT use and NSCLC risk in postmenopausal women. This association is strongest for ER-positive NSCLC. The multiple pathways of estrogen action, variation in response to estrogen by ER- and ER-β in lung tissue, and the interplay between estrogen, ER expression, smoking, and metabolic enzyme expression in the lung underscore the complexity of investigations into the role of exogenous estrogen in lung cancer risk. However, untangling tumor characteristics holds the promise of targeted interventions and treatments for this disease.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Ann G. Schwartz, Michele L. Cote, Sam C. Brooks, Fulvio Lonardo

Financial support: Ann G. Schwartz

Administrative support: Ann G. Schwartz, Geoffrey M. Prysak, Michele L. Cote

Provision of study materials or patients: Ann G. Schwartz, Fulvio Lonardo

Collection and assembly of data: Ann G. Schwartz, Angela S. Wenzlaff, Geoffrey M. Prysak, Valerie Murphy, Michele L. Cote, Fulvio Lonardo

Data analysis and interpretation: Ann G. Schwartz, Angela S. Wenzlaff, Geoffrey M. Prysak, Michele L. Cote, Sam C. Brooks, Debra F. Skafar, Fulvio Lonardo

Manuscript writing: Ann G. Schwartz, Angela S. Wenzlaff, Geoffrey M. Prysak, Valerie Murphy, Michele L. Cote, Sam C. Brooks, Debra F. Skafar, Fulvio Lonardo

Final approval of manuscript: Ann G. Schwartz, Angela S. Wenzlaff, Geoffrey M. Prysak, Valerie Murphy, Michele L. Cote, Sam C. Brooks, Debra F. Skafar, Fulvio Lonardo

	ACKNOWLEDGMENTS

 
We thank Steven Belinsky, PhD, for his comments and consultation and Lynda Forbes, Yvonne Bush, Kelly Montgomery, Pat Campagna, Gina Claeys, and the staff of the Metropolitan Detroit Cancer Surveillance System for data collection and management.

	NOTES

 
Supported by National Institutes of Health Grant No. R01-CA87895 and Contracts No. N01-PC35145 and P30CA22453.

Presented in part at the Annual Meeting of the North American Association of Central Cancer Registries, Detroit, MI, June 5-7, 2007.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted July 9, 2007; accepted September 18, 2007.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schwartz, A. G. Articles by Lonardo, F. Search for Related Content PubMed PubMed Citation Articles by Schwartz, A. G. Articles by Lonardo, F. Social Bookmarking                            What's this?