Estrogenic Steroid Hormones in Lung Cancer
Section snippets
ERs and Lung Cancer Survival
There are now many published reports examining ER status in relation to NSCLC patient survival (Table 1). Recently, high cytoplasmic ERβ-1 staining was identified as a negative prognostic factor for lung cancer, independent of other prognostic factors.22 Nuclear ERβ positivity was observed in the majority of lung cancer cases13, 14, 15, 16, 22 and was found to be a favorable prognostic indicator in some studies. In some reports, the prognostic significance was only observed in male patients or
Hormone Replacement and Lung Cancer Survival
Exposure to hormone replacement therapy (HRT) has negative effects on lung cancer survival. Ganti et al31 reported that a significant association between both a lower median age at lung cancer diagnosis and a shorter median survival time in women who used HRT around the time of diagnosis versus those who did not. This effect was more apparent in women who smoked, suggesting an interaction between estrogens and tobacco carcinogens. The Women’s Health Initiative, a randomized, placebo-controlled
Aromatase in Lung Cancer
CYP19, otherwise known as aromatase, a member of the cytochrome P450 family, catalyzes the conversion of androstenedione and testosterone to estrone and β-estradiol, respectively, and both CYP19 mRNA and protein have been detected in the lung.41, 42 High β-estradiol levels were detected by mass spectroscopy in intratumoral extracts of primary NSCLC.43 Several studies have now shown the ability of lung cancer cells to synthesize their own estrogen. Aromatase protein was expressed in NSCLC cell
Non-Genomic Estrogen Signaling and Interactions with Growth Factor Receptor Signaling Pathways
Although most breast cancer studies focus on nuclear actions of ERs, involving changes in gene transcription that take place over several hours or longer through direct binding of ERs to promoter elements of estrogen response genes, estrogen also can rapidly activate cytoplasmic kinase signaling in seconds to minutes. This rapid signaling is termed non-genomic and occurs via non-nuclear ERs located in the membrane or the cytoplasm. In breast cancer cells, an additional membrane ER was
Prs in Lung Cancer
There are two major isoforms of PR, PR-A and PR-B, which play different roles in modulating cellular responses to progesterone. PR is an estrogen response gene, and PR-positive breast cancers are usually more differentiated tumors that respond to anti-estrogen therapy. The ratio of PR-A to PR-B is thought to affect clinical outcome for breast cancer, with high levels of PR-A associating with more differentiation and better survival. There are several reports of expression of total PR by primary
ERs in Other Nonreproductive Malignancies
Expression of ER has been observed in tumors derived from other non-endocrine target tissues, such as head and neck squamous cell carcinoma (HNSCC). HNSCC tumors express ERs, although with variable results reported in the literature. Exogenous estrogen has been shown to stimulate HNSCC proliferation and invasion in vitro77 and to increase tumor growth in mice.78 Similar to lung cancer, estrogen has been shown to induce both genomic (transcriptional responses) as well as non-genomic (rapid
Summary
Research on steroid hormones in lung cancer is likely to benefit both men and women. Lung cancer in both male and female patients is ER- and PR-positive, as well as often being aromatase-positive. Cell lines derived from both sexes are responsive to estrogens, and show responses to therapeutic agents targeting the estrogen pathway. Endocrine-based therapeutic treatments may therefore be beneficial for both men and women. Endocrine therapies also have potential for lung cancer prevention.
Acknowledgments
This work was supported in part by the following grants: SPORE in Lung Cancer P50 090440 from the National Cancer Institute to J.M.S., Career Development Award from the SPORE in Lung Cancer P50 090440 to L.P.S., an award from the V Foundation for Cancer Research to J.M.S., and an award from the Lung Cancer Research Foundation to L.P.S.
The authors thank Carmella Campbell for assistance in preparation of the manuscript.
References (79)
- et al.
ER beta: identification and characterization of a novel human estrogen receptor
FEBS Lett
(1996) - et al.
The significance of estrogen receptor beta in 301 surgically treated non-small cell lung cancers
J Thorac Cardiovasc Surg
(2005) - et al.
Oestrogen receptor b over expression in males with non-small cell lung cancer is associated with better survival
Lung Cancer
(2008) - et al.
Cloning and characterization of human estrogen receptor beta isoforms
Biochem Biophys Res Commun
(1998) - et al.
Estrogen receptor beta (ERbeta) subtype-specific ligands increase transcription, p44/p42 mitogen activated protein kinase (MAPK) activation and growth in human non-small cell lung cancer cells
J Steroid Biochem Mol Biol
(2009) - et al.
Specificities of lung adenocarcinoma in women who have never smoked
J Thorac Oncol
(2013) - et al.
Menopausal effects on presentation, treatment, and survival of women with non-small cell lung cancer
Ann Thorac Surg
(2003) - et al.
Menopausal status of women may affect survival in advanced NSCLC: analysis of recent Eastern Cooperate Oncology Group (ECOG) studies using age of 60 years or older as a surrogate marker: P1-052
J Thorac Oncol
(2007) - et al.
Widespread tissue distribution of steroid sulfatase, 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD), 17 beta-HSD 5 alpha-reductase and aromatase activities in the rhesus monkey
Mol Cell Endocrinol
(1994) - et al.
Epidermal growth factor receptor overexpression correlates with a poor prognosis in completely resected non-small-cell lung cancer
Ann Oncol
(2004)
Estrogen receptor signaling pathways in human non-small cell lung cancer
Steroids
Antiestrogen fulvestrant enhances the antiproliferative effects of epidermal growth factor receptor inhibitors in human non-small cell lung cancer
J Thorac Oncol
Combining the multitargeted kinase inhibitor vandetanib with the antiestrogen fulvestrant enhances its antitumor effect in non-small cell lung cancer
J Thorac Oncol
The synergistic effect of EGFR tyrosine kinase inhibitor gefitinib in combination with aromtase inhibitor anastrozole in non-small cell lung cancer cell lines
Lung Cancer
Pilot study of gefitinib and fulvestrant in the treatment of post-menopausal women with advanced non-small cell lung cancer
Lung Cancer
Highly concordant coexpression of aromatase and estrogen receptor beta in non-small cell lung cancer
Hum Pathol
Steroid hormone receptors: long- and short-term integrators of the internal milieu and the external environment
Horm Metab Res
Differential ligand binding affinities of human estrogen receptor-α isoforms
PLOS One
Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling
Proc Natl Acad Sci USA
Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients
Clin Cancer Res
Tissue distribution of estrogen receptors alpha (ER-α) and beta (ER-β) mRNA in the midgestational human fetus
J Clin Endocrin Metab
Regulation of postnatal lung development and homeostasis by estrogen receptor β
Mol Cell Biol
Lung dysfunction causes systemic hypoxia in estrogen receptor beta knockout (ERbeta-/-) mice
Proc Natl Acad Sci USA
The role of estrogen receptor β in transplacental cancer prevention by indole-3-carbinol
Cancer Prev Res
Tissue-and time-dependent estrogen receptor activation in estrogen reporter mice
J Mol Endocrinol
Engineering of a mouse for the in vivo profiling of estrogen receptor activity
Mol Endocrinol
Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen
Cancer Res
Nuclear estrogen receptor beta in lung cancer: expression and survival differences by sex
Clin Cancer Res
Combined overexpression of EGFR and estrogen receptor alpha correlates with a poor outcome in lung cancer
Anticancer Res
Molecular cloning and characterization of human estrogen receptor beta: a potential inhibitor of estrogen action in human
Nucleic Acids Res
Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands
Cancer Res
Combined analysis of estrogen receptor b-1 and progesterone receptor expression identifies lung cancer patients with poor outcome
Clin Cancer Res
Expression of estrogen receptor beta 1 but not estrogen receptor beta 2 or alpha is linked to worse prognosis in stage I adenocarcinoma, in women, in a large epidemiological cohort but not in a smaller, single hospital based series
US Canadian Acad Pathol
Differential role of estrogen receptor beta in early versus metastatic non-small cell lung cancer
Horm Cancer
The expression of estrogen receptors b2,5 identifies and is associated with prognosis in non-small cell lung cancer
Endocrine
Ligand-independent antiapoptotic function of estrogen receptor-beta in lung cancer cells
Mol Endocrinol
Glucocorticoid and estrogen receptors are reduced in mitochondria of lung epithelial cells in asthma
PLoS One
Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience
J Clin Oncol
Hormone replacement therapy is associated with decreased survival in women with lung cancer
J Clin Oncol
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Financial disclosures/conflicts of interest: the authors have no disclosures relevant to this report.