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Gender is a risk factor for lung cancer
Medical Hypotheses 76 (2011) 328–331
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Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Gender is a risk factor for lung cancer James Gasperino ⇑ Section of Critical Care Medicine, Department of Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States
a r t i c l e
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Article history: Received 17 August 2010 Accepted 18 October 2010
a b s t r a c t Results of epidemiological studies suggest that, after one controls for the number of cigarettes smoked, women have a three times higher risk of getting lung cancer than men. Although the mechanism(s) explaining this gender-dependent difference in lung cancer risk is not known, it is thought that endocrine factors may play an important role. Normal human bronchial epithelial cells contain estrogen receptors and synthesize 17b-estradiol (E2) and estrone (E1), which can undergo further metabolism into the catechol estrogens, 4-hydroxyestradiol (4-OHE2) and 4-hydroxyestrone (4-OHE1), respectively. Catechol estrogens are formed from E2 by the actions of cytochrome p450 1B1 (CYP1B1). CYP1B1 is present in normal human bronchial epithelial) cells, and its activity is increased by cigarette smoking. Both 4-OHE1 and 4-OHE2 are mutagenic and carcinogenic and may exert their biological effects by inducing DNA adducts in cancer-related genes, including the tumor suppressor gene p53 and the proto-oncogene K-ras. Women with lung cancer have a different p53 mutational spectrum and a higher frequency of K-ras mutations than do men with lung cancer. Both clinical and basic research studies support the hypothesis that E2 and cigarette smoking are cofactors in lung carcinogenesis in women. More specifically, cigarette smoke stimulates metabolism of E2 into the genotoxic metabolites, 4-OHE1 and 4-OHE2, which interact with DNA in cancer-related genes, including the tumor suppressor gene, p53, and the proto-oncogene K-ras, two genes frequently mutated in patients with lung cancer. E2 may stimulate cellular proliferation and enhance tumor growth. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction
Hypothesis
Lung cancer is the leading cause of cancer deaths in men and women in the United Stated [1,2]. It is well established that cigarette smoking is the primary cause [1–8], although only 15% of smokers develop lung cancer, suggesting that other factors are involved [9–13]. In addition to cigarette smoking, gender influences the risk of lung cancer [14–23]. In fact, there is growing evidence in the literature that suggests that for women, the risk of all major histological types of lung cancer is approximately three times higher than for men, independent of the number of cigarettes smoked per day [14–16,19]. Moreover, among never-smokers, women also appear to have a higher risk of lung cancer than men, and adenocarcinoma is the most common histological subtype [22]. The biological explanation for this observation is not known; however, evidence suggests that endocrine factors, namely estrogens, play an important role in the pathogenesis of lung cancer in women smokers [24,25].
The proposed hypothesis suggests that both estrogens and exposure to tobacco carcinogens are important cofactors for lung carcinogenesis in women. The synergistic effect of these two cofactors begins with exposure to tobacco smoke, which contains polycyclic aromatic hydrocarbons (PAHs) and approximately 60 other known carcinogens. The PAHs stimulate the activity of cytochrome p450 1B1 (CYP1B1), a key enzyme in the metabolism of 17b-estradiol (E2). Both E2 and CYP1B1 are present in normal human bronchial epithelial cells. E2 is a major substrate for CYP1B1, and the enzyme activity leads to the production of highly active metabolites known as the catechol estrogens (4-OHE1, 4-OHE2). These genotoxic metabolites of the parent estrogen, E2, bind to the DNA of cancer-related genes present in normal bronchial epithelial cells of women smokers and act as initiators of carcinogenesis. In this sequence, the catechol estrogens form bulky DNA adducts in critical nucleotide sequences in cancer-related genes, including the tumor suppressor gene, p53, and the proto-oncogene K-ras, two genes frequently mutated in patients with lung cancer. The proposed hypothesis offers great insight into a clinical observation that has been greatly understudied, i.e., female gender as a risk factor for lung cancer.
⇑ Address: Department of Medicine, Drexel University College of Medicine, 245 N. 15th Street, Mail Stop 107, NCB 12th Floor, Philadelphia, PA 19102, United States. Tel.: +1 215 762 7011; fax: +1 215 762 8728. E-mail addresses: [email protected], [email protected] 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.10.030
J. Gasperino / Medical Hypotheses 76 (2011) 328–331
Evaluation of the hypothesis Female gender and lung cancer risk Lung cancer is the leading cause of cancer deaths in women living in the United States, and gender appears to be an important independent risk factor for developing this cancer. The literature supporting the clinical observation that female gender is an independent risk factor for lung cancer spans several decades and continues to grow. Risch and colleagues [16] used a case-control design to investigate gender differences in lung cancer risk as a function of histological type of lung cancer. When subjects with a 40-pack year smoking history were compared with nonsmokers, the risk of lung cancer in women was almost three times higher than that in men. Additionally, Harris and colleagues [17] investigated the independent associations of race and gender on lung cancer risk in a case-control study. African American and white subjects were stratified into two groups using Kreyberg’s classification, a superficial classification based on histological characteristics of the tumor. Squamous, oat cell, and large-cell cancer types were included in one group (K1); adenocarcinoma, alveolar, and undifferentiated cancers were included in the second group (K2). When patients with 5–8 g of cumulative tar exposure were compared with controls, the risk of lung cancer increased 20-fold in white men, 24-fold in African American men, 35-fold in white women, and 84-fold in African American women. These findings suggested that both race and gender influenced lung cancer risk. Further, Zang and Wynder used a retrospective study design to investigate the association between gender and lung cancer risk [19]. At every level of tobacco exposure, the risk of lung cancer in women was 1.2- to 1.5-fold higher than that in men. Their findings suggested that for the same lifetime exposure to cigarette smoke, women have a higher relative risk of lung cancer than men [19]. Most recently, Cerny et al. [20] evaluated the association between gender and lung cancer risk in a cohort of 670 patients with a cytological or histological diagnosis of lung cancer. Using a retrospective cohort design, they found that women with lung cancer had significantly less exposure to tobacco smoke than their male counterparts and on average were diagnosed at a younger age. In addition, women were more likely than men to have a diagnosis of adenocarcinoma of the lung [20]. More recently, Wakelee et al. [22] found that among never-smokers aged 40 to 79 years, the incidence rate of lung cancer was higher in women than in men. Using data from six cohort populations, they reported that the age-adjusted incident rate in women and men varied from 14.4 to 20.8 per 100,000 person-years and from 4.8 to 13.7 per 100,000 person-years, respectively [22].
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tive cohort of 36,588 peri- and postmenopausal women aged 50– 76 years from Washington State recruited between 2000 and 2002 as part of the Vitamins and Lifestyle [VITAL] Study to investigate the relationship between hormone replacement therapy and lung cancer risk (i.e., small cell lung cancer and non-small cell lung cancer) [27]. After using regression control to adjust for covariates, risk of lung cancer was associated with chronic use of estrogen plus progestin (i.e.,>10 years). Research studies are needed to link these important epidemiologic associations to the complex cellular actions of estrogens and tobacco carcinogens in the lung. The effects of endocrine factors on biologic systems are frequently modified by both environmental and genetic factors including, race [17], body fat distribution [28], and tumor type [22]. Epidemiologic studies examining the effects of endocrine factors and tobacco use on lung cancer risk in women must adjust for these variables to quantify their effect modification. Estrogen synthesis in the lung The lung actively metabolizes both androgen and estrogen [29– 33] and can synthesize E2 and E1 in situ from both testosterone and adrenal precursor hormones (Fig. 1). However, the enzymological characteristics of the lung appear to differ from those of classic reproductive tissues. For example, potent androgens are inactivated, and testosterone is stabilized within lung cells. Testosterone, instead of being converted into the potent androgen dihydrotestosterone (DHT), is readily converted into E2 by the actions of aromatase (CYP19) [33]. Similarly, E1 is formed from the adrenal precursor androstenedione by the activity of CYP19. Therefore the lung has two sources of intracellular E2: (1) E2 formed from de novo synthesis using precursor hormones as a substrate and (2) E2 formed in reproductive tissues and delivered to the lung. Estrogen as a carcinogen: Receptor-dependent and -independent processes The United States Health and Human Services 10th Report on Carcinogens has listed steroidal estrogens (e.g., E2) as known
Exogenous hormone use, smoking, and lung cancer Estrogen use and cigarette smoking may increase the risk of lung cancer in women [24,25]. Taoli and Wynder [25] used a case-control design to evaluate the risk of adenocarcinoma in women smokers who took estrogen replacement therapy (ERT). In this study, 180 women with adenocarcinoma of the lung were compared to 303 controls with nontobacco-related disease. The authors used unconditional logistic regression to calculate the odds ratios (OR) as estimates of relative risk. Women who smoked and used ERT had more than twice the risk of adenocarcinoma than smokers who did not use ERT (OR: 32.4 vs. 13.1, respectively). In contrast, women who used ERT but never smoked had no significant risk of adenocarcinoma (OR 1.0). Recent prospective investigations examining the relationship between hormone replacement therapy and lung cancer risk support and extend the results of earlier retrospective observations. Slatore et al. evaluated a prospec-
Fig. 1. Mechanisms of estrogen-induced carcinogenesis in the lung. The bronchial epithelial cell has two sources of E2. It can synthesize E2 from the adrenal precursor hormone dehydroepiandrosterone-sulfate or receive it by passive diffusion from the plasma (i.e., via its transport protein SHBG). Tobacco smoke, through the actions of its PAH constituents, increases the metabolism of E2 into catechol estrogen metabolites and damages DNA. These compounds are involved in cancer initiation. Alternatively, E2 can bind to the ER and stimulate genes regulating cell proliferation and tumor promotion. CYP19,(cytochrome p450; DHEA-S, dehydroepiandrosterone-sulfate; E2, 17b-estradiol; ER, estrogen receptor; 4-OHE2,4-hydroxyestradiol; 4OHE1, 4-hydroxyestrone; PAH, polycyclic aromatic hydrocarbon; SHBG, sex hormone-binding globulin.
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J. Gasperino / Medical Hypotheses 76 (2011) 328–331
carcinogens [34]. The carcinogenicity of E2 appears to reflect both receptor-mediated and receptor-independent actions of the hormone [35–39]. For example, E2 stimulates uncontrolled cellular proliferation and angiogenesis in endocrine target tissues through ligand-dependent activation of the estrogen receptor (ER) [35–39]. A number of investigators have identified either or both ER mRNA and functional ER protein in human lung tissue [40–52]. Fasco and colleagues found that ER-a was expressed more frequently in lung tissue obtained from women than in that obtained from men. In contrast, ER-b was expressed equally in lung tissue of both genders [49]. Women were more likely than men to express both receptor types in lung tissue specimens. Taken collectively, results of experimental studies indicate that E2 is capable of direct actions in the human lung, and gender may impact on its biological activity. A second pathway of estrogen-induced carcinogenesis is relevant to cancer initiation and involves metabolic activation of E2 [53–58]. This pathway does not require activation of the ER to alter cellular function; rather it involves DNA damage by metabolites of E2. E2 and estrone (E1) can be metabolized into catechol estrogens (e.g., 4-OHE2, 4-OHE1, respectively) by the 4-hydroxylase activity of cytochrome psa450 (CYP) 1B1(CYP1B1) [58–61]. CYP1B1 is expressed in the lung, and its activity is increased by cigarette smoking in vivo. Exposure of female mice to tobacco smoke caused induction of CYP1B1 as well as 10 other genes involved in early carcinogenic events. These important findings in animal models may explain observations of elevated estrogen metabolites in women smokers [62]. For instance, catechol estrogen levels are elevated in women smokers who take ERT relative to women who do not take ERT [63]. Thus, exogenous estrogen will also undergo metabolic activation into catechol estrogens in vivo. The mutagenicity of the catechol estrogens has been studied in animal models and in a variety of experimental systems [59–73]. It is thought that catechol estrogens must be activated into highly reactive intermediates before they can damage DNA. For example 4-OHE2 is first converted into its corresponding semiquinone and quinone intermediates [69,70]. The quinone form of 4-OHE2 can induce single strand breaks, 8-hydroxylation of guanine bases, and DNA adducts. Furthermore, covalent binding of the estrogen-quinone intermediate (3,4-estrogen quinone) to purine bases in DNA forms the unstable adduct 4-OHE1(E2)-1(alpha, beta)-N7Gua [69]. This depurinating DNA adduct formed from modification with either 4-OHE1 or 4-OHE2 is highly unstable and may cause G-to-T transversions [34–36,70]. Mutations in cancer-related genes: p53 and K-ras Mutations in the tumor suppressor gene p53 occur in over 50% of lung cancers [10]. In lung neoplasms of people who smoke, mutations in the p53 gene are found concentrated in its exons five, seven, and eight are located preferentially at methylated CpG sites. These sites are contained within codons 157, 158, 175, 238, 248, 273, and 282 of the p53 gene [10,74–77]. Approximately 40% of the mutations found at these tumor hot spots are G–T transversions [10], and these single base-pair mutations are twice as common in women with lung cancer than in their male counterparts [18]. Central to the proposed hypothesis is a mechanism whereby an activated estrogen metabolite is able to chemically modify tumor suppressor genes, including p53, leading to its mutation. Identification of catechol estrogen-DNA binding specificity for codons within tumor suppressor genes involved in lung cancer may provide a direct mechanism for estrogen-related cancers, including lung cancer. Another important gene in lung carcinogenesis is the protooncogene, K-ras. Mutations at codon 12 of the K-ras gene are present in 30% of smoking-related lung cancers, and this mutation has particular significance in women smokers. Nelson et al. found that
lung tumors from women smokers were three times more likely to have mutations at codon 12 of the K-ras gene (OR: 3.3) than were lung tumors from male smokers [73]. Moreover, this mutation predicted patient survival after adjustment for carcinogen exposure, age, sex, and stage of lung cancer. Sufficient epidemiological data are available to include female gender as an independent risk factor for lung cancer [14– 25,78,79]. Although the biological explanation is not known, a wealth of scientific evidence supports the hypothesis that E2 and cigarette smoking are cofactors in lung carcinogenesis (Fig. 1) [80]. Translational research studies are needed to understand the complex interactions between tobacco carcinogens, endocrine factors, and cancer-related genes. Tobacco carcinogens, both through their direct mutational actions and their ability to activate E2 into genotoxic catechol estrogens, may enhance the chemical modification of the tumor suppresser gene p53, and the proto-oncogene Kras. These cellular events may have important clinical implication in women smokers. Conflicts of interest statement None declared. References [1] Hammond EC. Smoking in relation to the death rates of one million men and women. Natl Cancer Inst Monogr 1966;19:127–204. [2] Satcher D. Women and Smoking: A Report of the Surgeon General. Atlanta GA: Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office of Smoking and Health, 2001. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=womsmk. Accessed 13 Aug 2010. [3] Bolego C, Poli A, Paoletti R. Smoking and gender. Cardiovasc Res 2002;53:568–76. [4] Denissenko MF, Pao A, Tang M, Pfeifer GP. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science 1996;274:430–2. [5] Doll R, Hill AB. The mortality of doctors in relation to their smoking habits; a preliminary report. Br Med J 1954;1:1451–5. [6] Husten CG, Shelton DM, Chrismon JH, Lin YC, Mowery P, Powell FA. Cigarette smoking and smoking cessation among older adults: United States, 1965–94. Tob Control 1997;6:175–80. [7] Escobedo LG, Peddicord JP. Smoking prevalence in US birth cohorts: the influence of gender and education. Am J Public Health 1996;86:231–6. [8] Collisharv NE, Lopez AD. The Tobacco Epidemic: A Global Public Health Emergency. Tobacco Alert. Geneva: World Health Organization; 1996. [9] National Research Council. Environmental Tobacco Smoke. Measuring Exposures and Assessing Health Effects. Washington DC, National Academy Press, 1986. [10] Greenblatt MS, Bennett WF, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 1994;54:4855–78. [11] Gonzalez F. The role of carcinogen-metabolizing enzyme polymorphisms in cancer susceptibility. Reprod Toxicol 1997;11:397–412. [12] Alexandrov K, Cascorbi I, Rojas M, Bouvier G, Kriek, Bartsch H. CYP1A1 and GSTM1 genotypes after benzo[a]pyrene DNA adducts in smokers’ lung: comparison with aromatic/hydrophobic adduct formation. Carcinogenesis 2002;23:1969–77. [13] Dresler CM, Fratelli C, Babb J, Everly L, Evans AA, Clapper ML. Gender differences in genetic susceptibility for lung cancer. Lung cancer 2000;30:153–60. [14] Pope M, Ashley M, Ferrence R. The carcinogenic and toxic effects of tobacco smoke: are women particularly susceptible? J Gender Spec Med 1999;2:45–51. [15] Osann KE, Anton-Culver H, Kurosaki T, Taylor T. Sex differences in lung-cancer risk associated with cigarette smoking. Int J Cancer 1993;54:44–8. [16] Risch H, Howe G, Jain M, Burch JD, Holowaty E, Miller A. Are female smokers at higher risk for lung cancer than male smokers? a case-control analysis by histologic type. Am J Epidemiol 1993;138:281–93. [17] Harris R, Zang E, Anderson J, Wynder E. Race and sex differences in lung cancer risk associated with cigarette smoking. Int J Epidemiol 1993;22:592–9. [18] Guinee D, Travis W, Trivers G, et al. Gender comparisons in human lung cancer: analysis of p53 mutations, anti-p53 serum antibodies and C-erb-2 expression. Carcinogenesis 1995;16:993–1002. [19] Zang EA, Wynder EL. Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 1996;88:183–92. [20] Cerny D, Cerny T, Ess S, D’Addario G, Fruh M. Lung cancer in the Canton of St. Gallen, Eastern Switzerland: sex-associated differences in smoking habits, disease presentation and survival. Onkologie 2009;32:569–73.
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Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Gender is a risk factor for lung cancer James Gasperino ⇑ Section of Critical Care Medicine, Department of Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States
a r t i c l e
i n f o
Article history: Received 17 August 2010 Accepted 18 October 2010
a b s t r a c t Results of epidemiological studies suggest that, after one controls for the number of cigarettes smoked, women have a three times higher risk of getting lung cancer than men. Although the mechanism(s) explaining this gender-dependent difference in lung cancer risk is not known, it is thought that endocrine factors may play an important role. Normal human bronchial epithelial cells contain estrogen receptors and synthesize 17b-estradiol (E2) and estrone (E1), which can undergo further metabolism into the catechol estrogens, 4-hydroxyestradiol (4-OHE2) and 4-hydroxyestrone (4-OHE1), respectively. Catechol estrogens are formed from E2 by the actions of cytochrome p450 1B1 (CYP1B1). CYP1B1 is present in normal human bronchial epithelial) cells, and its activity is increased by cigarette smoking. Both 4-OHE1 and 4-OHE2 are mutagenic and carcinogenic and may exert their biological effects by inducing DNA adducts in cancer-related genes, including the tumor suppressor gene p53 and the proto-oncogene K-ras. Women with lung cancer have a different p53 mutational spectrum and a higher frequency of K-ras mutations than do men with lung cancer. Both clinical and basic research studies support the hypothesis that E2 and cigarette smoking are cofactors in lung carcinogenesis in women. More specifically, cigarette smoke stimulates metabolism of E2 into the genotoxic metabolites, 4-OHE1 and 4-OHE2, which interact with DNA in cancer-related genes, including the tumor suppressor gene, p53, and the proto-oncogene K-ras, two genes frequently mutated in patients with lung cancer. E2 may stimulate cellular proliferation and enhance tumor growth. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction
Hypothesis
Lung cancer is the leading cause of cancer deaths in men and women in the United Stated [1,2]. It is well established that cigarette smoking is the primary cause [1–8], although only 15% of smokers develop lung cancer, suggesting that other factors are involved [9–13]. In addition to cigarette smoking, gender influences the risk of lung cancer [14–23]. In fact, there is growing evidence in the literature that suggests that for women, the risk of all major histological types of lung cancer is approximately three times higher than for men, independent of the number of cigarettes smoked per day [14–16,19]. Moreover, among never-smokers, women also appear to have a higher risk of lung cancer than men, and adenocarcinoma is the most common histological subtype [22]. The biological explanation for this observation is not known; however, evidence suggests that endocrine factors, namely estrogens, play an important role in the pathogenesis of lung cancer in women smokers [24,25].
The proposed hypothesis suggests that both estrogens and exposure to tobacco carcinogens are important cofactors for lung carcinogenesis in women. The synergistic effect of these two cofactors begins with exposure to tobacco smoke, which contains polycyclic aromatic hydrocarbons (PAHs) and approximately 60 other known carcinogens. The PAHs stimulate the activity of cytochrome p450 1B1 (CYP1B1), a key enzyme in the metabolism of 17b-estradiol (E2). Both E2 and CYP1B1 are present in normal human bronchial epithelial cells. E2 is a major substrate for CYP1B1, and the enzyme activity leads to the production of highly active metabolites known as the catechol estrogens (4-OHE1, 4-OHE2). These genotoxic metabolites of the parent estrogen, E2, bind to the DNA of cancer-related genes present in normal bronchial epithelial cells of women smokers and act as initiators of carcinogenesis. In this sequence, the catechol estrogens form bulky DNA adducts in critical nucleotide sequences in cancer-related genes, including the tumor suppressor gene, p53, and the proto-oncogene K-ras, two genes frequently mutated in patients with lung cancer. The proposed hypothesis offers great insight into a clinical observation that has been greatly understudied, i.e., female gender as a risk factor for lung cancer.
⇑ Address: Department of Medicine, Drexel University College of Medicine, 245 N. 15th Street, Mail Stop 107, NCB 12th Floor, Philadelphia, PA 19102, United States. Tel.: +1 215 762 7011; fax: +1 215 762 8728. E-mail addresses: [email protected], [email protected] 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.10.030
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Evaluation of the hypothesis Female gender and lung cancer risk Lung cancer is the leading cause of cancer deaths in women living in the United States, and gender appears to be an important independent risk factor for developing this cancer. The literature supporting the clinical observation that female gender is an independent risk factor for lung cancer spans several decades and continues to grow. Risch and colleagues [16] used a case-control design to investigate gender differences in lung cancer risk as a function of histological type of lung cancer. When subjects with a 40-pack year smoking history were compared with nonsmokers, the risk of lung cancer in women was almost three times higher than that in men. Additionally, Harris and colleagues [17] investigated the independent associations of race and gender on lung cancer risk in a case-control study. African American and white subjects were stratified into two groups using Kreyberg’s classification, a superficial classification based on histological characteristics of the tumor. Squamous, oat cell, and large-cell cancer types were included in one group (K1); adenocarcinoma, alveolar, and undifferentiated cancers were included in the second group (K2). When patients with 5–8 g of cumulative tar exposure were compared with controls, the risk of lung cancer increased 20-fold in white men, 24-fold in African American men, 35-fold in white women, and 84-fold in African American women. These findings suggested that both race and gender influenced lung cancer risk. Further, Zang and Wynder used a retrospective study design to investigate the association between gender and lung cancer risk [19]. At every level of tobacco exposure, the risk of lung cancer in women was 1.2- to 1.5-fold higher than that in men. Their findings suggested that for the same lifetime exposure to cigarette smoke, women have a higher relative risk of lung cancer than men [19]. Most recently, Cerny et al. [20] evaluated the association between gender and lung cancer risk in a cohort of 670 patients with a cytological or histological diagnosis of lung cancer. Using a retrospective cohort design, they found that women with lung cancer had significantly less exposure to tobacco smoke than their male counterparts and on average were diagnosed at a younger age. In addition, women were more likely than men to have a diagnosis of adenocarcinoma of the lung [20]. More recently, Wakelee et al. [22] found that among never-smokers aged 40 to 79 years, the incidence rate of lung cancer was higher in women than in men. Using data from six cohort populations, they reported that the age-adjusted incident rate in women and men varied from 14.4 to 20.8 per 100,000 person-years and from 4.8 to 13.7 per 100,000 person-years, respectively [22].
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tive cohort of 36,588 peri- and postmenopausal women aged 50– 76 years from Washington State recruited between 2000 and 2002 as part of the Vitamins and Lifestyle [VITAL] Study to investigate the relationship between hormone replacement therapy and lung cancer risk (i.e., small cell lung cancer and non-small cell lung cancer) [27]. After using regression control to adjust for covariates, risk of lung cancer was associated with chronic use of estrogen plus progestin (i.e.,>10 years). Research studies are needed to link these important epidemiologic associations to the complex cellular actions of estrogens and tobacco carcinogens in the lung. The effects of endocrine factors on biologic systems are frequently modified by both environmental and genetic factors including, race [17], body fat distribution [28], and tumor type [22]. Epidemiologic studies examining the effects of endocrine factors and tobacco use on lung cancer risk in women must adjust for these variables to quantify their effect modification. Estrogen synthesis in the lung The lung actively metabolizes both androgen and estrogen [29– 33] and can synthesize E2 and E1 in situ from both testosterone and adrenal precursor hormones (Fig. 1). However, the enzymological characteristics of the lung appear to differ from those of classic reproductive tissues. For example, potent androgens are inactivated, and testosterone is stabilized within lung cells. Testosterone, instead of being converted into the potent androgen dihydrotestosterone (DHT), is readily converted into E2 by the actions of aromatase (CYP19) [33]. Similarly, E1 is formed from the adrenal precursor androstenedione by the activity of CYP19. Therefore the lung has two sources of intracellular E2: (1) E2 formed from de novo synthesis using precursor hormones as a substrate and (2) E2 formed in reproductive tissues and delivered to the lung. Estrogen as a carcinogen: Receptor-dependent and -independent processes The United States Health and Human Services 10th Report on Carcinogens has listed steroidal estrogens (e.g., E2) as known
Exogenous hormone use, smoking, and lung cancer Estrogen use and cigarette smoking may increase the risk of lung cancer in women [24,25]. Taoli and Wynder [25] used a case-control design to evaluate the risk of adenocarcinoma in women smokers who took estrogen replacement therapy (ERT). In this study, 180 women with adenocarcinoma of the lung were compared to 303 controls with nontobacco-related disease. The authors used unconditional logistic regression to calculate the odds ratios (OR) as estimates of relative risk. Women who smoked and used ERT had more than twice the risk of adenocarcinoma than smokers who did not use ERT (OR: 32.4 vs. 13.1, respectively). In contrast, women who used ERT but never smoked had no significant risk of adenocarcinoma (OR 1.0). Recent prospective investigations examining the relationship between hormone replacement therapy and lung cancer risk support and extend the results of earlier retrospective observations. Slatore et al. evaluated a prospec-
Fig. 1. Mechanisms of estrogen-induced carcinogenesis in the lung. The bronchial epithelial cell has two sources of E2. It can synthesize E2 from the adrenal precursor hormone dehydroepiandrosterone-sulfate or receive it by passive diffusion from the plasma (i.e., via its transport protein SHBG). Tobacco smoke, through the actions of its PAH constituents, increases the metabolism of E2 into catechol estrogen metabolites and damages DNA. These compounds are involved in cancer initiation. Alternatively, E2 can bind to the ER and stimulate genes regulating cell proliferation and tumor promotion. CYP19,(cytochrome p450; DHEA-S, dehydroepiandrosterone-sulfate; E2, 17b-estradiol; ER, estrogen receptor; 4-OHE2,4-hydroxyestradiol; 4OHE1, 4-hydroxyestrone; PAH, polycyclic aromatic hydrocarbon; SHBG, sex hormone-binding globulin.
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carcinogens [34]. The carcinogenicity of E2 appears to reflect both receptor-mediated and receptor-independent actions of the hormone [35–39]. For example, E2 stimulates uncontrolled cellular proliferation and angiogenesis in endocrine target tissues through ligand-dependent activation of the estrogen receptor (ER) [35–39]. A number of investigators have identified either or both ER mRNA and functional ER protein in human lung tissue [40–52]. Fasco and colleagues found that ER-a was expressed more frequently in lung tissue obtained from women than in that obtained from men. In contrast, ER-b was expressed equally in lung tissue of both genders [49]. Women were more likely than men to express both receptor types in lung tissue specimens. Taken collectively, results of experimental studies indicate that E2 is capable of direct actions in the human lung, and gender may impact on its biological activity. A second pathway of estrogen-induced carcinogenesis is relevant to cancer initiation and involves metabolic activation of E2 [53–58]. This pathway does not require activation of the ER to alter cellular function; rather it involves DNA damage by metabolites of E2. E2 and estrone (E1) can be metabolized into catechol estrogens (e.g., 4-OHE2, 4-OHE1, respectively) by the 4-hydroxylase activity of cytochrome psa450 (CYP) 1B1(CYP1B1) [58–61]. CYP1B1 is expressed in the lung, and its activity is increased by cigarette smoking in vivo. Exposure of female mice to tobacco smoke caused induction of CYP1B1 as well as 10 other genes involved in early carcinogenic events. These important findings in animal models may explain observations of elevated estrogen metabolites in women smokers [62]. For instance, catechol estrogen levels are elevated in women smokers who take ERT relative to women who do not take ERT [63]. Thus, exogenous estrogen will also undergo metabolic activation into catechol estrogens in vivo. The mutagenicity of the catechol estrogens has been studied in animal models and in a variety of experimental systems [59–73]. It is thought that catechol estrogens must be activated into highly reactive intermediates before they can damage DNA. For example 4-OHE2 is first converted into its corresponding semiquinone and quinone intermediates [69,70]. The quinone form of 4-OHE2 can induce single strand breaks, 8-hydroxylation of guanine bases, and DNA adducts. Furthermore, covalent binding of the estrogen-quinone intermediate (3,4-estrogen quinone) to purine bases in DNA forms the unstable adduct 4-OHE1(E2)-1(alpha, beta)-N7Gua [69]. This depurinating DNA adduct formed from modification with either 4-OHE1 or 4-OHE2 is highly unstable and may cause G-to-T transversions [34–36,70]. Mutations in cancer-related genes: p53 and K-ras Mutations in the tumor suppressor gene p53 occur in over 50% of lung cancers [10]. In lung neoplasms of people who smoke, mutations in the p53 gene are found concentrated in its exons five, seven, and eight are located preferentially at methylated CpG sites. These sites are contained within codons 157, 158, 175, 238, 248, 273, and 282 of the p53 gene [10,74–77]. Approximately 40% of the mutations found at these tumor hot spots are G–T transversions [10], and these single base-pair mutations are twice as common in women with lung cancer than in their male counterparts [18]. Central to the proposed hypothesis is a mechanism whereby an activated estrogen metabolite is able to chemically modify tumor suppressor genes, including p53, leading to its mutation. Identification of catechol estrogen-DNA binding specificity for codons within tumor suppressor genes involved in lung cancer may provide a direct mechanism for estrogen-related cancers, including lung cancer. Another important gene in lung carcinogenesis is the protooncogene, K-ras. Mutations at codon 12 of the K-ras gene are present in 30% of smoking-related lung cancers, and this mutation has particular significance in women smokers. Nelson et al. found that
lung tumors from women smokers were three times more likely to have mutations at codon 12 of the K-ras gene (OR: 3.3) than were lung tumors from male smokers [73]. Moreover, this mutation predicted patient survival after adjustment for carcinogen exposure, age, sex, and stage of lung cancer. Sufficient epidemiological data are available to include female gender as an independent risk factor for lung cancer [14– 25,78,79]. Although the biological explanation is not known, a wealth of scientific evidence supports the hypothesis that E2 and cigarette smoking are cofactors in lung carcinogenesis (Fig. 1) [80]. Translational research studies are needed to understand the complex interactions between tobacco carcinogens, endocrine factors, and cancer-related genes. Tobacco carcinogens, both through their direct mutational actions and their ability to activate E2 into genotoxic catechol estrogens, may enhance the chemical modification of the tumor suppresser gene p53, and the proto-oncogene Kras. These cellular events may have important clinical implication in women smokers. Conflicts of interest statement None declared. References [1] Hammond EC. Smoking in relation to the death rates of one million men and women. Natl Cancer Inst Monogr 1966;19:127–204. [2] Satcher D. Women and Smoking: A Report of the Surgeon General. Atlanta GA: Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office of Smoking and Health, 2001. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=womsmk. Accessed 13 Aug 2010. [3] Bolego C, Poli A, Paoletti R. Smoking and gender. Cardiovasc Res 2002;53:568–76. [4] Denissenko MF, Pao A, Tang M, Pfeifer GP. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science 1996;274:430–2. [5] Doll R, Hill AB. The mortality of doctors in relation to their smoking habits; a preliminary report. Br Med J 1954;1:1451–5. [6] Husten CG, Shelton DM, Chrismon JH, Lin YC, Mowery P, Powell FA. Cigarette smoking and smoking cessation among older adults: United States, 1965–94. Tob Control 1997;6:175–80. [7] Escobedo LG, Peddicord JP. Smoking prevalence in US birth cohorts: the influence of gender and education. Am J Public Health 1996;86:231–6. [8] Collisharv NE, Lopez AD. The Tobacco Epidemic: A Global Public Health Emergency. Tobacco Alert. Geneva: World Health Organization; 1996. [9] National Research Council. Environmental Tobacco Smoke. Measuring Exposures and Assessing Health Effects. Washington DC, National Academy Press, 1986. [10] Greenblatt MS, Bennett WF, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 1994;54:4855–78. [11] Gonzalez F. The role of carcinogen-metabolizing enzyme polymorphisms in cancer susceptibility. Reprod Toxicol 1997;11:397–412. [12] Alexandrov K, Cascorbi I, Rojas M, Bouvier G, Kriek, Bartsch H. CYP1A1 and GSTM1 genotypes after benzo[a]pyrene DNA adducts in smokers’ lung: comparison with aromatic/hydrophobic adduct formation. Carcinogenesis 2002;23:1969–77. [13] Dresler CM, Fratelli C, Babb J, Everly L, Evans AA, Clapper ML. Gender differences in genetic susceptibility for lung cancer. Lung cancer 2000;30:153–60. [14] Pope M, Ashley M, Ferrence R. The carcinogenic and toxic effects of tobacco smoke: are women particularly susceptible? J Gender Spec Med 1999;2:45–51. [15] Osann KE, Anton-Culver H, Kurosaki T, Taylor T. Sex differences in lung-cancer risk associated with cigarette smoking. Int J Cancer 1993;54:44–8. [16] Risch H, Howe G, Jain M, Burch JD, Holowaty E, Miller A. Are female smokers at higher risk for lung cancer than male smokers? a case-control analysis by histologic type. Am J Epidemiol 1993;138:281–93. [17] Harris R, Zang E, Anderson J, Wynder E. Race and sex differences in lung cancer risk associated with cigarette smoking. Int J Epidemiol 1993;22:592–9. [18] Guinee D, Travis W, Trivers G, et al. Gender comparisons in human lung cancer: analysis of p53 mutations, anti-p53 serum antibodies and C-erb-2 expression. Carcinogenesis 1995;16:993–1002. [19] Zang EA, Wynder EL. Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 1996;88:183–92. [20] Cerny D, Cerny T, Ess S, D’Addario G, Fruh M. Lung cancer in the Canton of St. Gallen, Eastern Switzerland: sex-associated differences in smoking habits, disease presentation and survival. Onkologie 2009;32:569–73.
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