Regulation of Endogenous Gene Expression in Human Non–Small Cell Lung Cancer Cells by Estrogen Receptor Ligands

Hershberger, Pamela A.; Vasquez, A. Cecilia; Kanterewicz, Beatriz; Land, Stephanie R.; Siegfried, Jill M.; Nichols, Mark

doi:10.1158/0008-5472.can-04-2694

Cited by 153 publications

(142 citation statements)

References 39 publications

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“…The higher prevalence for methylation of this gene in spontaneous tumors from the B6C3F1 mouse parallels our previous findings in spontaneous lung tumors from the A/J mouse (20). This finding suggests that silencing of the ER-a gene is important for the development of tumors arising spontaneously in the mouse lung possibly through effects on cell proliferation (27,28). Few studies have examined methylation of this gene in human lung tumors.…”

Section: Discussionmentioning

confidence: 99%

Gene Promoter Hypermethylation in Mouse Lung Tumors

Vuillemenot

Hutt

Belinsky

2006

Molecular Cancer Research

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The mouse is a good model for evaluating the efficacy of chemopreventive agents for lung cancer. Gene silencing by promoter hypermethylation is a critical component for the development and progression of lung cancer and an emerging target for preventive intervention by demethylating agents. Genes methylated in mouse lung tumors could serve as biomarkers to evaluate the effectiveness of demethylating agents for preventing lung cancer and causing gene reexpression in vivo. The purpose of the current study was to evaluate a panel of genes inactivated by promoter hypermethylation in human lung cancer for silencing by this epigenetic mechanism in murine lung tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), cigarette smoke, or arising spontaneously. Cadherin-13, estrogen receptor-A, progesterone receptor, and runt-related transcription factor-3 were frequently methylated in mouse lung tumor-derived cell lines, whereas cadherin-1 and suppressor of cytokine signaling-1 were not. Methylation within these four genes was associated with lack of expression that could be restored after treatment with 5-aza-2V-deoxycytidine and with methylation within the CpG island of each gene. Methylation-specific PCR revealed that methylation of these four genes occurred at prevalences of 24% to 69% in primary lung tumors arising spontaneously or induced by exposure to cigarette smoke or NNK. Estrogen receptor-A methylation was more frequent in spontaneously occurring lung cancer than cigarette smoke -induced or NNK-induced lung cancer, whereas runt-related transcription factor-3 showed the opposite relationship. Thus, genes can be targeted for inactivation by methylation, depending on exposure history. This study indicates that methylation events frequently observed in human lung cancer are recapitulated in the mouse model and identifies four potential biomarkers for assessing intervention approaches for reversing epigenetically mediated gene silencing. (Mol Cancer Res 2006;4(4):267 -73)

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Section: Discussionmentioning

confidence: 99%

Gene Promoter Hypermethylation in Mouse Lung Tumors

Vuillemenot

Hutt

Belinsky

2006

Molecular Cancer Research

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“…There are a limited number of studies with conflicting data regarding ERa and ERb expression in human lung cancer and in lung cancer cell lines (Croxtall et al 1994, Caltagirone et al 1997, Omoto et al 2001, Radzikowska et al 2002, Stabile et al 2002, 2005, Hershberger et al 2005 and only two studies directly comparing ER expression in lung cancer specimens and cell lines in males and females (Fasco et al 2002, Mollerup et al 2002. One study reported similar levels of ERa and ERb in females and males (Mollerup et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Gender difference in the activity but not expression of estrogen receptors α and β in human lung adenocarcinoma cells

Dougherty¹,

Mazhawidza²,

Bohn³

et al. 2006

Endocr Relat Cancer

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The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender-dependent factors in the etiology of lung cancer. We evaluated estrogen receptor (ER) a and b expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts. Full-length ERa and ERb proteins were expressed in all cell lines with higher ERb than ERa. Although estradiol (E 2 ) binding was similar, E 2 stimulated proliferation only in cells from females, and this response was inhibited by anti-estrogens 4-hydroxytamoxifen (4-OHT) and ICI 182,780. In contrast, E 2 did not stimulate replication of lung adenocarcinoma cells from males and 4-OHT or ICI did not block cell proliferation. Similarly, transcription of an estrogen response element-driven reporter gene was stimulated by E 2 in lung adenocarcinoma cells from females, but not males. Progesterone receptor (PR) expression was increased by E 2 in two out of five adenocarcinoma cell lines from females, but none from males. E 2 decreased E-cadherin protein expression in some of the cell lines from females, as it did in MCF-7 breast cancer cells, but not in the cell lines from males. Thus, ERa and ERb expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells. On the other hand, coactivator DRIP205 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells. DRIP205 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males.

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“…The ER-α gene has been associated with elevated lung cancer risk (12,20,21,(26)(27)(28). However, the association between polymorphisms of XbaI and PvuII in the ER-α gene and the risk of developing lung cancer remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…ERs reportedly inhibit proliferation and invasion of breast and lung cancer cells (7,28). Extranuclear forms of ER play a role in promoting downstream signaling for hormone-mediated proliferation and survival of breast as well as lung cancers and offer a new target for anti-tumor therapy (22).…”

Section: Discussionmentioning

confidence: 99%

Association of estrogen receptor α gene PvuII and XbaI polymorphisms with non-small cell lung cancer

Chang

Cheng

et al. 2011

Oncology Letters

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Abstract. Single nucleotide polymorphisms (SNPs) of the estrogen receptor (ER)-α have been found to be associated with various diseases at significantly different frequencies. However, whether any relationship exists between ER-α polymorphisms and lung cancer remains to be determined. In this study, 84 non-smoking, female, non-small cell lung cancer patients with various stages of disease and 234 cancer-free reference controls were enrolled to examine the association of ER-α polymorphisms in lung cancer. Two restriction SNP sites, PvuII and XbaI, in the first intron of the ER-α gene were genotyped by polymerase chain reaction-restriction fragment length polymorphism. The frequencies of the PvuII-XbaI haplotypes and genotypes in a Taiwanese population were revealed for the first time. Although the genotypic frequencies of two polymorphic sites of ER-α were in linkage disequilibrium for the lung cancer group (χ 2 =50.013, d.f.=4) and reference controls (χ 2 =60.797, d.f.=4); and 7 and 8 combined genotypes were present, respectively, the distribution and the major genotypes are different in the two groups (p<0.0001). The p-values for PvuII and XbaI genotypes were significantly different between the lung cancer and reference controls. The PP genotype presence was found to be significantly lower in the lung cancer group (P=0.005), whereas presence of the xx genotype was significantly higher (P= 0.042). These findings suggested that the PP genotype had a lower risk of lung cancer; whereas the xx genotype had a higher risk. In comparison with other studies conducted in various populations, it is of note that the pX haplotype frequency of this study was higher than that of other studies, whereas the px haplotype was lower. Moreover, the Xx genotypic frequency of XbaI polymorphisms in the ER-α gene of the reference control group was found to be extremely high, whereas the xx genotypic frequency was extremely low. In conclusion, PvuII-XbaI polymorphisms of the ER-α gene were found to be associated with the risk, but not cancer severity, of non-small cell lung cancer in a Taiwanese population.

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Regulation of Endogenous Gene Expression in Human Non–Small Cell Lung Cancer Cells by Estrogen Receptor Ligands

Cited by 153 publications

References 39 publications

Gene Promoter Hypermethylation in Mouse Lung Tumors

Gene Promoter Hypermethylation in Mouse Lung Tumors

Gender difference in the activity but not expression of estrogen receptors α and β in human lung adenocarcinoma cells

Association of estrogen receptor α gene PvuII and XbaI polymorphisms with non-small cell lung cancer

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