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Serum estrogen and tumor-positive estrogen receptor-alpha are strong prognostic classifiers of non-small-cell lung cancer survival in both men and women.

ABSTRACT: The role of tumor estrogen receptors (ERs) and serum estrogen in lung cancer is inconclusive. We investigated the hypothesis that ERs and functional single-nucleotide polymorphisms in the estrogen biosynthesis pathway are associated with poorer lung cancer survival. Lung cancer patients (n?=?305) from a National Cancer Institute-Maryland (NCI-MD) case-case cohort in the Baltimore metropolitan area were used as a test cohort. To validate, 227 cases from the NCI-MD case-control cohort and 293 cases from a Norwegian lung cancer cohort were studied. Information on demographics, tobacco and reproductive histories was collected in an interviewer-administered questionnaire. Serum estrogen, progesterone, tumor messenger RNA expression of hormone receptors and germ line DNA polymorphisms were analyzed for associations with lung cancer survival. Patients in the highest tertile of serum estrogen had worse survival in all three cohorts (P combined?

SUBMITTER: Olivo-Marston SE

PROVIDER: S-EPMC2981456 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Serum estrogen and tumor-positive estrogen receptor-alpha are strong prognostic classifiers of non-small-cell lung cancer survival in both men and women.

Olivo-Marston Susan E SE Mechanic Leah E LE Mollerup Steen S Bowman Elise D ED Remaley Alan T AT Forman Michele R MR Skaug Vidar V Zheng Yun-Ling YL Haugen Aage A Harris Curtis C CC

Carcinogenesis 20100820 10

The role of tumor estrogen receptors (ERs) and serum estrogen in lung cancer is inconclusive. We investigated the hypothesis that ERs and functional single-nucleotide polymorphisms in the estrogen biosynthesis pathway are associated with poorer lung cancer survival. Lung cancer patients (n = 305) from a National Cancer Institute-Maryland (NCI-MD) case-case cohort in the Baltimore metropolitan area were used as a test cohort. To validate, 227 cases from the NCI-MD case-control cohort and 293 case ...[more]

PMID: 20729390

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Project description:BackgroundThe glucocorticoid receptor (NR3C1, GR) is frequently downregulated in breast tumors, and evidence suggests it acts as a tumor suppressor in estrogen receptor-positive (ER+) breast cancer. We previously found that methylation of the GR promoter CpG island represses gene expression and occurs in ER+ breast tumors. In this study, the prognostic and predictive value of GR methylation was examined in ER+ patients from the CCTG MA.12 clinical trial of tamoxifen versus placebo in women with early breast cancer.MethodsWe developed a targeted multiplex bisulfite next-generation sequencing assay to detect methylation at multiple GR promoter regions in DNA from formalin-fixed paraffin-embedded (FFPE) samples. Following validation in a small cohort of breast tumors, ER+ FFPE tumor samples from MA.12 (n?=?208) were tested. Survival analyses evaluated the impact of GR promoter methylation on patient overall survival (OS) and disease-free survival (DFS).ResultsAn analysis of TCGA data found that GR methylation is prevalent in ER+ tumors and is associated with decreased gene expression and analysis of public microarray data (KM Plotter) linked decreased GR expression to a poor outcome. In MA.12, two GR promoter regions (U and C) each had prognostic value, but with opposite effects on the outcome. U methylation was associated with poor OS (HR?=?1.79, P?=?0.041) whereas C methylation was associated with better OS (HR?=?0.40, P?=?0.040) and DFS (HR?=?0.49, P?=?0.037). The classification of patients based on the methylation status of the two regions was prognostic for OS (P?=?0.006) and DFS (P?=?0.041) and revealed a group of patients (U methylated, C unmethylated) with very poor outcomes. Placebo-treated patients in this high-risk group had worse OS (HR?=?2.86, P?=?0.002) and DFS (HR?=?2.09, P?=?0.014) compared to the rest of the cohort.ConclusionRegion-specific GR promoter methylation was an independent prognostic marker for patient survival and identified a subset of patients with poor prognosis, particularly without tamoxifen treatment. These findings provide a foundation for future studies into GR methylation as a promising prognostic biomarker in ER+ breast cancer.

Project description:BackgroundSin3A is an evolutionarily conserved transcriptional repressor which regulates gene expression as part of the multi-protein Sin3 repressive complex. It functions as a scaffold upon which proteins with enzymatic activity dock, including chromatin modifying histone deacetylases. Although regulation of transcription by Sin3A has been studied in detail, little is understood about the function of Sin3A in cancer cells. We previously showed that Sin3A is expressed in breast cancer cells and is a repressor of estrogen receptor-alpha (ERα, ESR1) gene expression. Here, we expand our previous studies to elucidate the function of Sin3A in the control of gene expression and growth of breast cancer cells.ResultsAnalysis of gene expression following knockdown of Sin3A revealed changes in both basal and regulated gene transcription. Genes of known importance in breast cancer and estrogen signaling, including ERBB2, PGR, MYC, CLU, and NCOA2, were among those identified as Sin3A-responsive. The mechanism of Sin3A action varied among genes and was found to be mediated through both HDAC1/2 -dependent and -independent activities. Loss of Sin3A inhibited breast cancer cell growth by increasing apoptosis without affecting cell cycle progression. Analysis of both ERα-positive and ERα-negative cell lines revealed that the effects of Sin3A on growth were cell-type specific, as Sin3A expression promoted maximum growth of only the ERα-positive cells, and, notably, Sin3A protein itself was increased by estrogen. Further gene expression experiments revealed that Sin3A repressed expression of key apoptotic genes, including TRAIL, TRAILR1, CASP10, and APAF1, in ERα-positive, but not ERα-negative, cell lines, which could provide a mechanistic explanation for cell-type differences in growth.ConclusionsThis study identifies Sin3A as a regulator of gene expression, survival, and growth in ERα-positive breast cancer cells. Sin3A regulates the transcription of genes involved in breast cancer and apoptosis and acts through multiple mechanisms not limited to histone deacetylase function. These findings reveal previously undescribed functions of Sin3A in breast cancer and provide evidence for an important role of this transcriptional repressor in ERα-positive tumor cell growth.

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Serum estrogen and tumor-positive estrogen receptor-alpha are strong prognostic classifiers of non-small-cell lung cancer survival in both men and women.

Publications

Serum estrogen and tumor-positive estrogen receptor-alpha are strong prognostic classifiers of non-small-cell lung cancer survival in both men and women.

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