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1.  The role of estrogen, progesterone and aromatase in human non-small-cell lung cancer 
Lung cancer management  2012;1(4):259-272.
SUMMARY
Lung cancer is the leading cause of cancer-related deaths in both men and women worldwide. Despite advances in treatment, patients have few effective therapeutic options and survival rates remain low. Emerging evidence suggests that the hormones estrogen and progesterone play a key role in the progression of non-small-cell lung cancer (NSCLC). The aromatase enzyme, which is responsible for a key step in estrogen biosynthesis, elicits higher levels of estrogen in lung tumors as well as in metastases compared with nonmalignant tissues. Thus, aromatase may prove to be a key predictive biomarker for treatment of NSCLC. Epidemiologic and preclinical data show estrogens play a critical role in lung tumor development and progression. Two estrogen receptors, α and β, are expressed in normal and in cancerous lung epithelium, and estrogen promotes gene transcription that stimulates cell proliferation and inhibits cell death. Furthermore, expression of both forms of estrogen receptor, progesterone receptor and aromatase in NSCLC specimens has been correlated with worse clinical outcomes. Combination therapies that include estrogen receptor downregulators and aromatase inhibitors are currently being assessed in Phase I–II clinical trials among patients with advanced NSCLC. Results will help guide future lung cancer management decisions, with a goal of achieving more effective and less toxic treatments for patients.
doi:10.2217/lmt.12.44
PMCID: PMC3643508  PMID: 23650476
2.  Targeting Aromatase and Estrogen Signaling in Human Non-Small Cell Lung Cancer 
Lung cancer has become increasingly common in women, and gender differences in the physiology and pathogenesis of the disease have suggested a role for estrogens. In the lung recent data have shown local production of estrogens from androgens via the action of aromatase enzyme and higher levels of estrogen in tumor tissue as compared with surrounding normal lung tissue. High levels of aromatase expression are also maintained in metastases as compared with primary tumors. Consistent with these findings, clinical studies suggest that aromatase expression may be a useful predictive biomarker for prognosis in the management of non-small cell lung cancer (NSCLC), the most common form of lung malignancy. Low levels of aromatase associate with a higher probability of long-term survival in older women with early stage NSCLC. Treatment of lung NSCLC xenografts in vivo with an aromatase inhibitor (exemestane) alone or combined with standard cisplatin chemotherapy elicits a significant reduction in tumor progression as compared to paired controls. Further, lung cancer progression is also governed by complex interactions between estrogen and growth factor signaling pathways to stimulate the growth of NSCLC as well as tumor-associated angiogenesis. We find that combination therapy with the multitargeted growth factor receptor inhibitor vandetanib and the estrogen receptor antagonist fulvestrant inhibit tumor growth more effectively than either treatment administered alone. Thus, incorporation of antiestrogen treatment strategies in standard antitumor therapies for NSCLC may contribute to improved patient outcome, an approach that deserves to be tested in clinical trials.
doi:10.1111/j.1749-6632.2009.04116.x
PMCID: PMC2782616  PMID: 19250205
non-small cell lung cancer (NSCLC); aromatase; CYP19; estrogen receptor (ER); epidermal growth factor receptor (EGFR); vascular endothelial growth factor (VEGF) receptor; anastrazole; exemestane; fulvestrant; vandetanib
3.  Estrogen Receptor Signaling in Lung Cancer 
Seminars in oncology  2009;36(6):524.
Lung cancer has long been thought of as a cancer that mainly affects men, but over the past several decades, because of the high increase in tobacco use by women, there has been a corresponding dramatic increase in lung cancer among women. Since 1998, lung cancer deaths in women have surpassed those caused by breast cancer in the United States. Annual lung cancer deaths among women in the US also currently surpass those caused by breast, ovarian, and cervical cancers combined. Women are more likely than men to be diagnosed with adenocarcinoma and small-cell carcinoma of the lung compared to squamous cell carcinoma, and never smokers diagnosed with lung cancer are almost three times more likely to be female than male. These observations in the population, coupled to the findings that both estrogen receptors and aromatase, the enzyme that synthesizes 17β-estradiol, are expressed by lung tumors, suggest a role for female steroid hormones in control of lung cancer growth. Pre-clinical data and clinical data are increasingly emerging to support this concept, and to suggest that a local production of estrogen and expression of ERs occurs in lung tumors that rise in men as well as women. An additional protein that recognizes 17β-estradiol with high affinity, GPR30, is also expressed in lung tumors at high levels and may be responsible for some of the proliferation signals induced by estrogen.
doi:10.1053/j.seminoncol.2009.10.004
PMCID: PMC2818861  PMID: 19995644
4.  Aromatase Expression Predicts Survival in Women with Early-Stage Non–Small Cell Lung Cancer 
Cancer research  2007;67(21):10484-10490.
Estrogen signaling is critical in the progression of tumors that bear estrogen receptors. In most patients with breast cancer, inhibitors that block interactions of estrogen with its receptors or suppress the production of endogenous estrogens are important interventions in the clinic. Recent evidence now suggests that estrogen also contributes to the pathogenesis of non–small cell lung cancer (NSCLC). We used a human lung cancer xenograph model system to analyze the effect of aromatase or estradiol on tumor growth. We further examined the level of protein expression of aromatase in 422 patients with NSCLC using a high-density tissue microarray. Results were confirmed and validated on an independent patient cohort (n = 337). Lower levels of aromatase predicted a greater chance of survival in women 65 years and older. Within this population, the prognostic value of aromatase was greatest in earlier stage lung cancer (stage I/II). In addition, for women with no history of smoking, lower aromatase levels were a strong predictor of survival. Our findings implicate aromatase as an early-stage predictor of survival in some women with NSCLC. We predict that women whose lung cancers have higher levels of aromatase might be good candidates for targeted treatment with aromatase inhibitors.
doi:10.1158/0008-5472.CAN-07-2607
PMCID: PMC3581354  PMID: 17974992
5.  Expression Levels of Estrogen Receptor Beta in Conjunction with Aromatase Predict Survival in Non-Small Cell Lung Cancer 
Estrogen signaling pathways may play a significant role in the pathogenesis of non-small cell lung cancers (NSCLC) as evidenced by the expression of aromatase and estrogen receptors (ERα and ERβ) in many of these tumors. Here we examine whether ERα and ERβ levels in conjunction with aromatase define patient groups with respect to survival outcomes and possible treatment regimens. Immunohistochemistry was performed on a high-density tissue microarray with resulting data and clinical information available for 377 patients. Patients were subdivided by gender, age and tumor histology, and survival data was determined using the Cox proportional hazards model and Kaplan-Meier curves. Neither ERα nor ERβ alone were predictors of survival in NSCLC. However, when coupled with aromatase expression, higher ERβ levels predicted worse survival in patients whose tumors expressed higher levels of aromatase. Although this finding was present in patients of both genders, it was especially pronounced in women ≥ 65 years old, where higher expression of both ERβ and aromatase indicated a markedly worse survival rate than that determined by aromatase alone. Conclusion: Expression of ERβ together with aromatase has predictive value for survival in different gender and age subgroups of NSCLC patients. This predictive value is stronger than each individual marker alone. Our results suggest treatment with aromatase inhibitors alone or combined with estrogen receptor modulators may be of benefit in some subpopulations of these patients.
doi:10.1016/j.lungcan.2011.03.009
PMCID: PMC3175023  PMID: 21511357
NSCLC; tissue microarray; aromatase; estrogen receptor; immunohistochemistry; prognosis
6.  Invited Commentary: The Etiology of Lung Cancer in Men Compared With Women 
American Journal of Epidemiology  2013;177(7):613-616.
Lung cancer is the leading cause of cancer death among women in the United States and other Western nations. The predominant cause of lung cancer in women is active cigarette smoking. Secondhand exposure to tobacco smoke is another important cause. The hypothesis that women are more susceptible than men to smoking-induced lung cancer has not been supported by the preponderance of current data, as noted by De Matteis et al. (Am J Epidemiol. 2013;177(7):601–612) in the accompanying article. However, aspects of lung cancer in men and women continue to indicate potential male-female differences in the etiology of lung cancer, based on several observations: 1) among never smokers, women have higher lung cancer incidence rates than men; 2) there is evidence that estrogen may contribute to lung cancer risk and progression; and 3) there are different clinical characteristics of lung cancer in women compared with men, such as the higher percentage of adenocarcinomas in never smokers, the greater prevalence of epidermal growth factor receptor gene (EGFR) mutations in adenocarcinomas among never smokers, and better prognosis. Considered in total, observations such as these offer enticing clues that, even amid cigarette smoking and other commonalities in the etiology of lung cancer in men and women, distinct differences may remain to be delineated that could potentially be of scientific and clinical relevance.
doi:10.1093/aje/kws444
PMCID: PMC3657534  PMID: 23425628
cigarettes; estrogen; lung cancer; men; secondhand smoke exposure; sex; smoking; women
7.  Antiproliferative effect of exemestane in lung cancer cells 
Molecular Cancer  2009;8:109.
Background
Recent evidence suggests that estrogen signaling may be involved in the pathogenesis of non-small cell lung cancer (NSCLC). Aromatase is an enzyme complex that catalyses the final step in estrogen synthesis and is present in several tissues, including the lung. In the current study we investigated the activity of the aromatase inhibitor exemestane in human NSCLC cell lines H23 and A549.
Results
Aromatase expression was detected in both cell lines. H23 cells showed lower protein and mRNA levels of aromatase, compared to A549 cells. Exemestane decreased cell proliferation and increased apoptosis in both cell lines, 48 h after its application, with A549 exhibiting higher sensitivity than H23 cells. Aromatase protein and mRNA levels were not affected by exemestane in A549 cells, whereas an increase in both protein and mRNA levels was observed in H23 cells, 48 h after exemestane application. Moreover, an increase in cAMP levels was found in both cell lines, 15 min after the administration of exemestane. In addition, we studied the effect of exemestane on epidermal growth factor receptor (EGFR) localization and activation. Exemestane increased EGFR activation 15 min after its application in H23 cells. Furthermore, we demonstrated a translocation of EGFR from cell membrane, 24 h after the addition of exemestane in H23 cells. No changes in EGFR activation or localization were observed in A549 cells.
Conclusion
Our findings suggest an antiproliferative effect of exemestane on NSCLC cell lines. Exemestane may be more effective in cells with higher aromatase levels. Further studies are needed to assess the activity of exemestane in NSCLC.
doi:10.1186/1476-4598-8-109
PMCID: PMC2789046  PMID: 19930708
8.  Impact of Neuro-Psychological Factors on Smoking-Associated Lung Cancer 
Cancers  2014;6(1):580-594.
Smoking has been extensively documented as a risk factor for all histological types of lung cancer and tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons reproducibly cause lung cancer in laboratory rodents. However, the most common lung cancer, non-small cell lung cancer (NSCLC), frequently develops in never smokers and is particularly common in women and African Americans, suggesting that factors unrelated to smoking significantly impact this cancer. Recent experimental investigations in vitro and in animal models have shown that chronic psychological stress and the associated hyperactive signaling of stress neurotransmitters via β-adrenergic receptors significantly promote the growth and metastatic potential of NSCLC. These responses were caused by modulation in the expression and sensitization state of nicotinic acetylcholine receptors (nAChRs) that regulate the production of stress neurotransmitters and the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Similar changes in nAChR-mediated neurotransmitter production were identified as the cause of NSCLC stimulation in vitro and in xenograft models by chronic nicotine. Collectively, these data suggest that hyperactivity of the sympathetic branch of the autonomic nervous system caused by chronic psychological stress or chronic exposure to nicotinic agonists in cigarette smoke significantly contribute to the development and progression of NSCLC. A recent clinical study that reported improved survival outcomes with the incidental use of β-blockers among patients with NSCLC supports this interpretation.
doi:10.3390/cancers6010580
PMCID: PMC3980616  PMID: 24633083
smoking; non-small cell lung cancer; nicotinic receptors; β-adrenergic receptors; sympathicus hyperactivity; psychological stress
9.  Estrogen Signaling in Lung Cancer: An Opportunity for Novel Therapy 
Cancers  2012;4(4):969-988.
Lung cancer is the leading cause of cancer death in U.S. and represents a major public health burden. Epidemiologic data have suggested that lung cancer in women may possess different biological characteristics compared to men, as evidenced by a higher proportion of never-smokers among women with lung cancer. Emerging data indicate that female hormones such as estrogen and progesterone play a significant role in lung carcinogenesis. It has been reported that estrogen and progesterone receptors are expressed in lung cancer cell lines as well as in patient-derived tumors. Hormone related risk factors such as hormone replacement therapy have been implicated in lung carcinogenesis and several preclinical studies show activity of anti-estrogen therapy in lung cancer. In this review, we summarize the emerging evidence for the role of reproductive hormones in lung cancer and implications for lung cancer therapy.
doi:10.3390/cancers4040969
PMCID: PMC3712734  PMID: 24213497
lung cancer; estrogen; progesterone; aromatase; hormone receptors
10.  Notch signaling in lung cancer 
Summary
Lung cancer is the leading cause of cancer-related deaths in the Western world. Lungs can be affected by a number of histologically diverse malignancies. Nonetheless, the vast majority of lung cancers are classified as non-small cell lung cancer (NSCLC). Despite extensive research on different therapeutic regimens, the overall 5-year survival of patients diagnosed with NSCLC (all stages) is a dismal 15%. Although strongly correlated with tobacco smoke, there is an increasing NSCLC morbidity in individuals who have never smoked. The pattern of genetic lesions found in NSCLC derived from smokers and never-smokers appears to be different. This fact led to the hypothesis that different, still unidentified carcinogens are responsible for lung cancer onset in never-smokers. All the above considerations compel the scientific community to find novel therapeutic targets to fight such a deadly disease.
In recent years critical pathways governing embryonic development have been increasingly linked to cancer. Here we will focus on the role of Notch signaling in lung cancer. Notch receptors’ activity can be blocked following different strategies, thus representing a promising alternative/complement to the arsenal of therapeutic strategies currently used to treat lung cancer.
doi:10.1586/era.10.158
PMCID: PMC3380361  PMID: 21504320
lung cancer; cancer progenitor cells; Notch signaling; hypoxia; cancer stem cells; Notch signaling inhibition
11.  Intratumoral localization and activity of 17β-hydroxysteroid dehydrogenase type 1 in non-small cell lung cancer: a potent prognostic factor 
Background
Estrogens were recently demonstrated to be synthesized in non-small cell lung carcinomas (NSCLCs) via aromatase activity and aromatase inhibitor (AI) did suppressed estrogen receptor (ER) positive NSCLC growth. However, other enzymes involved in intratumoral production and metabolism of estrogens, i.e. 17β-hydroxysteroid dehydrogenases (i.e. 17βHSD1 and 17βHSD2) and others have not been studied. Therefore, in this study, we examined the clinical/ biological significance of 17β-hydroxysteroid dehydrogenases in NSCLCs.
Methodology
Archival materials obtained from 103 NSCLC patients were immunohistochemically evaluated using anti-17βHSD1 and anti-17βHSD2 antibodies. The findings of immunohistochemistry were then correlated with intratumoral estrone (E1) and estradiol (E2) concentration, clinicopathological factors and overall survival of the patients. We further employed NSCLC cell lines, A549 and LK87 to study the functional significance of 17βHSD1, in vitro.
Results
A higher 17βHSD1 immunoreactivity tended to be positively associated with aromatase (p=0.057) and tumor stage (p=0.055) whereas a higher 17βHSD2 immunoreactivity was positively associated with a squamous cell and adenosquamous cell carcinomas subtypes (p=0.031), tumor stage (p=0.004), T factor of TNM classification (p=0.010), maximum tumor diameter (p=0.002) and tended to be associated with N factor of TMN classification (p=0.065). A higher 17βHSD1 immunoreactivity was also significantly associated with lower intratumoral E1 concentration (p=0.040) and a higher intratumoral E2/E1 concentration ratio (p=0.028). On the other hand a higher 17βHSD2 immunoreactivity was significantly associated with higher intratumoral E1 concentration (p=0.035). Results of multivariate regression analysis demonstrated an increased 17βHSD1 immunoreactivity in tumor cells as an independent negative prognostic factor (HR= 2.83, p=0.007). E1 treatment in 17βHSD1 positive NSCLC cells, A549 and LK87, resulted in E2 production (p<0.0001) and enhanced cell proliferation, which was abrogated effectively by 17βHSD1 siRNA knockdown (p<0.0001). In addition, aromatase inhibitor treatment resulted in 17βHSD1 up regulation in both A549 and LK87 cells.
Conclusion
Results of our present study suggest that 17βHSD1 may be considered an important prognostic factor in NSCLC patients and targeting 17βHSD1 activity may further improve the clinical response in estrogen responsive NSCLC patients.
doi:10.1186/1479-5876-11-167
PMCID: PMC3724709  PMID: 23837683
Lung cancer; Intratumoral estrogens; 17β-hydroxysteroid dehydrogenase; Targeted therapy
12.  Changes in Aromatase (CYP19) Gene Promoter Usage in Non-Small Cell Lung Cancer 
In humans, aromatase (CYP19) gene expression is regulated via alternative promoters. Activation of each promoter gives rise to a CYP19 mRNA species with a unique 5′-untranslated region. Inhibition of aromatase has been reported to downregulate lung tumor growth. The genetic basis for CYP19 gene expression and aromatase activity in lung cancer remains poorly understood. We analyzed tissues from 15 patients with non-small cell lung cancer (NSCLC) to evaluate CYP19 promoter usage and promoter-specific aromatase mRNA levels in NSCLC tumor tissues and adjacent non-malignant tissues. CYP19 promoter usage was determined by multiplex RT-PCR and aromatase mRNA levels were measured with real-time RT-PCR. In non-malignant tissues, aromatase mRNA was primarily derived from activation of CYP19 promoter I.4. Although promoter I.4 usage was also dominant in tumor tissues, I.4 activation was significantly lower compared with adjacent non-malignant tissues. Activity of promoters I.3, I.1 and I.7 was significantly higher in tumor tissues compared with non-malignant tissues. In 4 of 15 cases of non-small cell lung cancer, switching from CYP19 promoter I.4 to the alternative promoters II, I.1 or I.7 was observed. In 9 cases, there were significantly higher levels of aromatase mRNA in lung tumor tissues compared with adjacent non-malignant tissues. These findings suggest aberrant activation of alternative CYP19 promoters that may lead to upregulation of local aromatase expression in some cases of NSCLC. Further studies are needed to examine the impact of alternative CYP19 promoter usage on local estrogen levels and lung tumor growth.
doi:10.1016/j.lungcan.2011.01.003
PMCID: PMC3118270  PMID: 21320735
non-small cell lung cancer; estrogen; aromatase; CYP19; promoter; promoter usage
13.  COPD increases the risk of squamous histological subtype in smokers who develop non-small cell lung carcinoma 
Thorax  2004;59(8):679-681.
Background: Squamous cell carcinoma has a stronger association with tobacco smoking than other non-small cell lung cancers (NSCLC). A study was undertaken to determine whether chronic obstructive pulmonary disease (COPD) is a risk factor for the squamous cell carcinoma histological subtype in smokers with surgically resectable NSCLC.
Methods: Using a case-control design, subjects with a surgically confirmed diagnosis of squamous cell carcinoma were enrolled from smokers undergoing lung resection for NSCLC in the District Hospital of Ferrara, Italy. Control subjects were smokers who underwent lung resection for NSCLC in the same hospital and had a surgically confirmed diagnosis of NSCLC of any histological type other than squamous cell.
Results: Eighty six cases and 54 controls (mainly adenocarcinoma, n = 50) were enrolled. The presence of COPD was found to increase the risk for the squamous cell histological subtype by more than four times. Conversely, the presence of chronic bronchitis was found to decrease the risk for this histological subtype by more than four times. Among patients with chronic bronchitis (n = 77), those with COPD had a 3.5 times higher risk of having the squamous cell histological subtype.
Conclusions: These data suggest that, among smokers with surgically resectable NSCLC, COPD is a risk factor for the squamous cell histological subtype and chronic bronchitis, particularly when not associated with COPD, is a risk factor for the adenocarcinoma histological subtype.
doi:10.1136/thx.2003.018291
PMCID: PMC1747095  PMID: 15282388
14.  Cell Density is a Critical Determinant of Aromatase Expression in Adipose Stromal Cells 
Obesity is associated with an increased risk of breast cancer among post-menopausal women. This is at least partly due to excessive estrogen production in adipose tissue of obese women. Aromatase, the key enzyme in estrogen biosynthesis, is an important target in endocrine therapy for estrogen receptor (ER)-positive postmenopausal breast cancer. In this study we show that high confluency of human adipose stromal cells (ASCs) cultured in vitro can significantly stimulate aromatase gene expression and reduce the expression of breast tumor suppressor BRCA1 and members of the NR4A orphan nuclear family. Furthermore, small interfering RNA (siRNA)-mediated knockdown of Nurr1, a member of the NR4A family, substantially increased aromatase expression. Lastly, we found that the cell density-triggered inducibility of aromatase expression varies in ASCs isolated from different disease-free individuals. Our finding highlights the impact of increased cell number on estrogen biosynthesis as in the case of excessive adiposity.
doi:10.1016/j.jsbmb.2009.12.001
PMCID: PMC2826521  PMID: 19969081
15.  Prevention of tobacco carcinogen-induced lung cancer in female mice using antiestrogens 
Carcinogenesis  2012;33(11):2181-2189.
Increasing evidence shows that estrogens are involved in lung cancer proliferation and progression, and most human lung tumors express estrogen receptor β (ERβ) as well as aromatase. To determine if the aromatase inhibitor anastrozole prevents development of lung tumors induced by a tobacco carcinogen, alone or in combination with the ER antagonist fulvestrant, ovariectomized female mice received treatments with the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) along with daily supplements of androstenedione, the substrate for aromatase. Placebo, anastrozole and/or fulvestrant were administered in both an initiation and a promotion protocol of lung tumorigenesis. The combination of fulvestrant and anastrozole given during NNK exposure resulted in significantly fewer NNK-induced lung tumors (mean = 0.5) compared with placebo (mean = 4.6, P < 0.001), fulvestrant alone (mean = 3.4, P < 0.001) or anastrozole alone (mean = 2.8, P = 0.002). A significantly lower Ki67 cell proliferation index was also observed compared with single agent and control treatment groups. Beginning antiestrogen treatment after NNK exposure, when preneoplastic lesions had already formed, also yielded maximum antitumor effects with the combination. Aromatase expression was found mainly in macrophages infiltrating preneoplastic and tumorous areas of the lungs, whereas ERβ was found in both macrophages and tumor cells. Antiestrogens, especially in combination, effectively inhibited tobacco carcinogen-induced murine lung tumorigenesis and may have application for lung cancer prevention. An important source of estrogen synthesis may be inflammatory cells that infiltrate the lungs in response to carcinogens, beginning early in the carcinogenesis process. ERβ expressed by inflammatory and neoplastic epithelial cells in the lung may signal in response to local estrogen production.
doi:10.1093/carcin/bgs260
PMCID: PMC3584962  PMID: 22859269
16.  Deaths in Canada from lung cancer due to involuntary smoking. 
Recently published evidence indicates that involuntary smoking causes an increased risk of lung cancer among nonsmokers. Information was compiled on the proportion of people who had never smoked among victims of lung cancer, the risk of lung cancer for nonsmokers married to smokers and the prevalence of such exposure. On the basis of these data we estimate that 50 to 60 of the deaths from lung cancer in Canada in 1985 among people who had never smoked were caused by spousal smoking; about 90% occurred in women. The total number of deaths from lung cancer attributable to exposure to tobacco smoke from spouses and other sources (mainly the workplace) was derived by applying estimated age- and sex-specific rates of death from lung cancer attributable to such exposure to the population of Canadians who have never smoked; about 330 deaths from lung cancer annually are attributable to such exposure.
PMCID: PMC1491963  PMID: 3567810
17.  Weight Gain Increases Human Aromatase Expression in Mammary Gland 
Adulthood weight gain predicts estrogen receptor-positive breast cancer. Because local estrogen excess in the breast likely contributes to cancer development, and aromatase is the key enzyme in estrogen biosynthesis, we investigated the role of local aromatase expression in weight gain-associated breast cancer risk in a humanized aromatase (Aromhum) mouse model containing the coding region and the 5′-regulatory region of the human aromatase gene. Compared with littermates on normal chow, female Aromhum mice on a high fat diet gained more weight, and had a larger mammary gland mass with elevated total human aromatase mRNA levels via promoters I.4 and II associated with increased levels of their regulators TNFα and C/EBPβ. There was no difference in total human aromatase mRNA levels in gonadal white adipose tissue. Our data suggest that diet-induced weight gain preferentially stimulates local aromatase expression in the breast, which may lead to local estrogen excess and breast cancer risk.
doi:10.1016/j.mce.2012.01.027
PMCID: PMC3312968  PMID: 22342815
aromatase; overweight; weight gain; obesity; mammary; breast cancer
18.  Association of Epidermal Growth Factor Receptor Mutations with Metastatic Presentations in Non-Small Cell Lung Cancer 
ISRN Oncology  2011;2011:756265.
We performed this retrospective study to assess the association of epidermal growth factor receptor (EGFR) with metastatic presentations in advanced non-small cell lung cancer (NSCLC). The data from 125 patients with stage III or IV NSCLC were analyzed. We detected EGFR mutations in 36 NSCLC patients. EGFR mutations were predominant in never-smokers (P < .001), patients with adenocarcinomas (P < .001), and female patients (P < .001). When the metastatic sites were analyzed, pleural metastases were associated with a high incidence of EGFR mutations (P = .028). Particularly, pleural metastases with minimal effusion (PMME) were associated with EGFR mutational status (P = .001). Patients with N3 lesions were less likely to harbor EGFR mutations (P = .033). On multivariate analysis, N3 lesions (P = .017) and PMME (P < .001) remained significant factors for EGFR mutations. EGFR mutations may be associated with different presentations of pleural and N3 nodal metastases.
doi:10.5402/2011/756265
PMCID: PMC3195961  PMID: 22091430
19.  Genome-Wide Association Study of Lung Cancer in Korean Non-Smoking Women 
Journal of Korean Medical Science  2013;28(6):840-847.
Lung cancer in never-smokers ranks as the seventh most common cause of cancer death worldwide, and the incidence of lung cancer in non-smoking Korean women appears to be steadily increasing. To identify the effect of genetic polymorphisms on lung cancer risk in non-smoking Korean women, we conducted a genome-wide association study of Korean female non-smokers with lung cancer. We analyzed 440,794 genotype data of 285 cases and 1,455 controls, and nineteen SNPs were associated with lung cancer development (P < 0.001). For external validation, nineteen SNPs were replicated in another sample set composed of 293 cases and 495 controls, and only rs10187911 on 2p16.3 was significantly associated with lung cancer development (dominant model, OR of TG or GG, 1.58, P = 0.025). We confirmed this SNP again in another replication set composed of 546 cases and 744 controls (recessive model, OR of GG, 1.32, P = 0.027). OR and P value in combined set were 1.37 and < 0.001 in additive model, 1.51 and < 0.001 in dominant model, and 1.54 and < 0.001 in recessive model. The effect of this SNP was found to be consistent only in adenocarcinoma patients (1.36 and < 0.001 in additive model, 1.49 and < 0.001 in dominant model, and 1.54 and < 0.001 in recessive model). Furthermore, after imputation with HapMap data, we found regional significance near rs10187911, and five SNPs showed P value less than that of rs10187911 (rs12478012, rs4377361, rs13005521, rs12475464, and rs7564130). Therefore, we concluded that a region on chromosome 2 is significantly associated with lung cancer risk in Korean non-smoking women.
doi:10.3346/jkms.2013.28.6.840
PMCID: PMC3677999  PMID: 23772147
Lung Neoplasms; Genome-Wide Association Study; Non-Smoking Women
20.  In situ aromatase expression in primary tumor is associated with estrogen receptor expression but is not predictive of response to endocrine therapy in advanced breast cancer 
BMC Cancer  2009;9:185.
Background
New, third-generation aromatase inhibitors (AIs) have proven comparable or superior to the anti-estrogen tamoxifen for treatment of estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer. AIs suppress total body and intratumoral estrogen levels. It is unclear whether in situ carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved in the synthesis of aromatase, has been suggested as a surrogate marker for aromatase expression.
Methods
Primary tumor material was retrospectively collected from 88 patients who participated in a randomized clinical trial comparing the AI letrozole to the anti-estrogen tamoxifen for first-line treatment of advanced breast cancer. Semi-quantitative immunohistochemical (IHC) analysis was performed for ER, PR, COX-2 and aromatase using Tissue Microarrays (TMAs). Aromatase was also analyzed using whole sections (WS). Kappa analysis was applied to compare association of protein expression levels. Univariate Wilcoxon analysis and the Cox-analysis were performed to evaluate time to progression (TTP) in relation to marker expression.
Results
Aromatase expression was associated with ER, but not with PR or COX-2 expression in carcinoma cells. Measurements of aromatase in WS were not comparable to results from TMAs. Expression of COX-2 and aromatase did not predict response to endocrine therapy. Aromatase in combination with high PR expression may select letrozole treated patients with a longer TTP.
Conclusion
TMAs are not suitable for IHC analysis of in situ aromatase expression and we did not find COX-2 expression in carcinoma cells to be a surrogate marker for aromatase. In situ aromatase expression in tumor cells is associated with ER expression and may thus point towards good prognosis. Aromatase expression in cancer cells is not predictive of response to endocrine therapy, indicating that in situ estrogen synthesis may not be the major source of intratumoral estrogen. However, aromatase expression in combination with high PR expression may select letrozole treated patients with longer TTP.
Trial registration
Sub-study of trial P025 for advanced breast cancer.
doi:10.1186/1471-2407-9-185
PMCID: PMC2702392  PMID: 19531212
21.  Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing 
Carcinogenesis  2012;33(7):1270-1276.
Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole-exome sequencing in 31 NSCLCs and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas and squamous cell carcinomas, two major histologies in NSCLC. In addition to identifying previously known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and RB1), the analysis revealed many genes not previously implicated in this malignancy. Notably, a novel gene CSMD3 was identified as the second most frequently mutated gene (next to TP53) in lung cancer. We further demonstrated that loss of CSMD3 results in increased proliferation of airway epithelial cells. The study provides unprecedented insights into mutational processes, cellular pathways and gene networks associated with lung cancer. Of potential immediate clinical relevance, several highly mutated genes identified in our study are promising druggable targets in cancer therapy including ALK, CTNNA3, DCC, MLL3, PCDHIIX, PIK3C2B, PIK3CG and ROCK2.
doi:10.1093/carcin/bgs148
PMCID: PMC3499051  PMID: 22510280
22.  IGDB.NSCLC: integrated genomic database of non-small cell lung cancer 
Nucleic Acids Research  2011;40(D1):D972-D977.
Lung cancer is the most common cause of cancer-related mortality with more than 1.4 million deaths per year worldwide. To search for significant somatic alterations in lung cancer, we analyzed, integrated and manually curated various data sets and literatures to present an integrated genomic database of non-small cell lung cancer (IGDB.NSCLC, http://igdb.nsclc.ibms.sinica.edu.tw). We collected data sets derived from hundreds of human NSCLC (lung adenocarcinomas and/or squamous cell carcinomas) to illustrate genomic alterations [chromosomal regions with copy number alterations (CNAs), gain/loss and loss of heterozygosity], aberrant expressed genes and microRNAs, somatic mutations and experimental evidence and clinical information of alterations retrieved from literatures. IGDB.NSCLC provides user friendly interfaces and searching functions to display multiple layers of evidence especially emphasizing on concordant alterations of CNAs with co-localized altered gene expression, aberrant microRNAs expression, somatic mutations or genes with associated clinicopathological features. These significant concordant alterations in NSCLC are graphically or tabularly presented to facilitate and prioritize as the putative cancer targets for pathological and mechanistic studies of lung tumorigenesis and for developing new strategies in clinical interventions.
doi:10.1093/nar/gkr1183
PMCID: PMC3245121  PMID: 22139933
23.  Pack Years of Cigarette Smoking as a Prognostic Factor in Patients with Stage IIIB/IV Non-Small Cell Lung Cancer 
Cancer  2010;116(3):670-675.
Background
We undertook this study to characterize the relationship between survival of patients with stage IIIB/IV Non-Small Cell Lung Cancer (NSCLC) and pack years of cigarette smoking.
Methods
We analyzed data from patients with stage IIIB/IV NSCLC who had completed a prospective smoking questionnaire. We evaluated the impact of pack years of cigarette smoking, age, sex, Karnofsky Performance Status (KPS), and presence of weight loss >5% on overall survival using univariate and multivariate analyses.
Results
Smoking history and clinical data were available for 2,010 patients with stage IIIB/IV NSCLC (1004 women, 1006 men). Seventy percent (1409) smoked >15 pack years, 13% (270) were former and current smokers who had smoked ≤ 15 pack years, and 16% (331) were never smokers (<100 lifetime cigarettes). Never smokers had a longer median survival relative to former or current smokers (17.8 months vs 11.3 months, log rank p<0.001). Among smokers, patients with ≤ 15 pack year history of smoking had a longer median survival than patients who had smoked > 15 pack years (14.6 months vs 10.8 months, log rank p =0.03). As the number of pack years increased, the median overall survival decreased (log rank p <0.001). Multivariate analysis showed that history of smoking was an independent prognostic factor (Hazard Ratio 1.36; p<0.001).
Conclusions
More cigarette smoking, measured in pack years, was associated with decreased survival after diagnosis of stage IIIB/IV NSCLC. Trials assessing survival in stage IIIB/IV NSCLC should report detailed cigarette smoking history for all patients.
doi:10.1002/cncr.24813
PMCID: PMC2815173  PMID: 20029977
24.  Survival following non-small cell lung cancer among Asian/Pacific Islander, Latina, and non-Hispanic White women who have never smoked 
BACKGROUND
Lung cancer is the leading cause of cancer death among US Asian/Pacific Islander (API) and Latina women, despite low smoking prevalence. This study examined survival patterns following non-small cell lung cancer in a population-based sample of lung cancer cases from the San Francisco Bay Area Lung Cancer Study (SFBALCS).
METHODS
Women diagnosed with lung cancer from 1998–2003 and 2005–2008 and identified through the Greater Bay Area Cancer Registry were telephone-screened for eligibility for the SFBALCS. The screener data were linked to the cancer registry data to determine follow-up. This analysis included 187 non-Hispanic White, 23 US-born Latina, 32 foreign-born Latina, 30 US-born API, and 190 foreign-born API never smokers diagnosed with lung cancer and followed through 2008.
RESULTS
All-cause survival was poorer among APIs (hazard ratio (HR) and 95% confidence interval (CI) = 1.7 (1.0–2.8) among US-born APIs; 1.2 (0.9–1.5) among foreign-born APIs), and Latinas (HR (95% CI) = 2.1 (1.2–3.6) among US-born Latinas; 1.4 (0.9–2.3) among foreign-born Latinas), relative to non-Hispanic Whites. These survival differences were not explained by differences in selected sociodemographic or clinical factors.
CONCLUSIONS
Further research should focus on factors such as cultural behaviors, access to or attitudes toward health care, and genetic variations, as possible explanations for these striking racial/ethnic differences.
IMPACT
Latina and API female never smokers diagnosed with lung cancer were up to two-times more likely to die than non-Hispanic Whites, highlighting the need for additional research to identify the underlying reasons for the disparities, as well as heightened clinical awareness.
doi:10.1158/1055-9965.EPI-10-0965
PMCID: PMC3070404  PMID: 21239685
lung cancer survival; Asian; Latina; Hispanic; never smokers; nativity
25.  Relation between smoking history and gene expression profiles in lung adenocarcinomas 
BMC Medical Genomics  2012;5:22.
Background
Lung cancer is the worldwide leading cause of death from cancer. Tobacco usage is the major pathogenic factor, but all lung cancers are not attributable to smoking. Specifically, lung cancer in never-smokers has been suggested to represent a distinct disease entity compared to lung cancer arising in smokers due to differences in etiology, natural history and response to specific treatment regimes. However, the genetic aberrations that differ between smokers and never-smokers’ lung carcinomas remain to a large extent unclear.
Methods
Unsupervised gene expression analysis of 39 primary lung adenocarcinomas was performed using Illumina HT-12 microarrays. Results from unsupervised analysis were validated in six external adenocarcinoma data sets (n=687), and six data sets comprising normal airway epithelial or normal lung tissue specimens (n=467). Supervised gene expression analysis between smokers and never-smokers were performed in seven adenocarcinoma data sets, and results validated in the six normal data sets.
Results
Initial unsupervised analysis of 39 adenocarcinomas identified two subgroups of which one harbored all never-smokers. A generated gene expression signature could subsequently identify never-smokers with 79-100% sensitivity in external adenocarcinoma data sets and with 76-88% sensitivity in the normal materials. A notable fraction of current/former smokers were grouped with never-smokers. Intriguingly, supervised analysis of never-smokers versus smokers in seven adenocarcinoma data sets generated similar results. Overlap in classification between the two approaches was high, indicating that both approaches identify a common set of samples from current/former smokers as potential never-smokers. The gene signature from unsupervised analysis included several genes implicated in lung tumorigenesis, immune-response associated pathways, genes previously associated with smoking, as well as marker genes for alveolar type II pneumocytes, while the best classifier from supervised analysis comprised genes strongly associated with proliferation, but also genes previously associated with smoking.
Conclusions
Based on gene expression profiling, we demonstrate that never-smokers can be identified with high sensitivity in both tumor material and normal airway epithelial specimens. Our results indicate that tumors arising in never-smokers, together with a subset of tumors from smokers, represent a distinct entity of lung adenocarcinomas. Taken together, these analyses provide further insight into the transcriptional patterns occurring in lung adenocarcinoma stratified by smoking history.
doi:10.1186/1755-8794-5-22
PMCID: PMC3447685  PMID: 22676229
Lung cancer; Smoking; Gene expression analysis; Adenocarcinoma; EGFR; Never-smokers; Immune response

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