Expression, Function, and Clinical Implications of the Estrogen Receptor β in Human Lung Cancers

Omoto, Yoko; Kobayashi, Yasuhito; Nishida, Kazunori; Tsuchiya, Eiju; Eguchi, Hidetaka; Nakagawa, Ken; Ishikawa, Yuichi; Yamori, Takao; Iwase, Hirotaka; Fujii, Yoshitaka; Warner, Margaret; Gustafsson, Jan‐Åke; Hayashi, S.

doi:10.1006/bbrc.2001.5158

Cited by 181 publications

(96 citation statements)

References 36 publications

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“…Subsequently, numerous studies have reported on the expression of ERβ in various cancers, including our observations in breast , lung (Omoto et al 2001), and stomach (Matsuyama et al 2002). Immunohistochemical studies suggest that ERβ tends to be expressed in ERα-positive breast cancers, and that there are ERα and ERβ co-expressing cells in human breast cancer.…”

Section: Introductionsupporting

confidence: 54%

The expression and function of estrogen receptor alpha and beta in human breast cancer and its clinical application.

Eguchi

Tanimoto

et al. 2003

Endocrine-Related Cancer

162

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The overexpression of estrogen receptor α (ERα) is frequently observed in the early stage of breast cancer. We previously reported that the specific promoter of the ERα gene is responsible for this enhanced transcription of the gene, and identified the cis-acting elements which play an important role in its transcription. Furthermore, methylation of the ERα gene promoters also contribute to the regulation of gene transcription. Elucidation of these mechanisms of ERα gene expression may provide useful information for the early detection and chemoprevention of breast cancer. On the other hand, the expression of ERβ has been reported in breast cancer. We have also assessed the significance and function of ERβ and its variant types in breast cancer, and suggest that ERβ and ERβcx specifically suppress the function of ERα through different mechanisms. ERβ isoforms may be important functional modulators of the estrogen-signaling pathway in breast cancer cells, and might affect the clinical outcome of patients. Moreover, to address the role of these ERs on the estrogen-dependent growth of breast cancer cells and to develop a diagnostic tool, we have analyzed the gene expression profiles of estrogen-responsive genes using cDNA microarray. Based on these results, the expression of several candidate genes in breast cancer tissues were analyzed by real-time RT-PCR and by immunohistochemical techniques, in order to discover new predictive factors for the endocrine therapy of patients with breast cancer. These studies could provide new clues for the elucidation of the estrogen-dependent mechanisms of cancer and the clinical benefits for patients.

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Section: Introductionsupporting

confidence: 54%

The expression and function of estrogen receptor alpha and beta in human breast cancer and its clinical application.

Eguchi

Tanimoto

et al. 2003

Endocrine-Related Cancer

162

View full text Add to dashboard Cite

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“…Estrogens have been shown to act via ERh in the lung to directly regulate platelet-derived growth factor A and granulocyte-macrophage colony-stimulating factor, key regulators of alveolar formation and surfactant homeostasis, respectively (32). Furthermore, Omoto et al has shown that ERh expression is stronger in cancerous samples than normal samples (33). A better understanding of the role of ERh in the lung is necessary to lead to novel strategies and targets for lung cancer treatment and prevention.…”

Section: Discussionmentioning

confidence: 99%

Combined Targeting of the Estrogen Receptor and the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Shows Enhanced Antiproliferative Effects

Stabile

Lyker²,

Gubish³

et al. 2005

Cancer Research

291

301

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Identifying new effective therapeutic treatments for lung cancer is critical to improving overall patient survival. We have targeted both the estrogen receptor (ER) and the epidermal growth factor receptor (EGFR) pathways using an ER antagonist, fulvestrant (''Faslodex''), and the selective EGFR tyrosine kinase inhibitor, gefitinib (''Iressa''), in nonsmall cell lung cancer (NSCLC) cells. Rapid activation of phospho-EGFR and phospho-p44/p42 mitogen-activated protein kinase by estrogen was observed, indicating nonnuclear ER transactivation of EGFR. Additionally, EGFR protein expression was down-regulated in response to estrogen and up-regulated in response to fulvestrant in vitro, suggesting that the EGFR pathway is activated when estrogen is depleted in NSCLC cells. Cell growth and apoptosis were examined in several NSCLC lines that express varying amounts of ERB, EGFR, and Neu but no full-length ERa. One cell line contained an EGFR mutation. Cells were exposed to 10 nmol/L estrogen and 10 ng/mL EGF and either 1 Mmol/L fulvestrant or 1 Mmol/L gefitinib alone or in combination. In all cell lines, the drug combination decreased cell proliferation up to 90% and increased apoptosis 2-fold. The relative responses to gefitinib and fulvestrant were similar regardless of ER and EGFR expression and mutation status. In an in vivo lung tumor xenograft model, the drug combination decreased tumor volume in severe combined immunodeficient mice by f60% compared with 49% and 32% for gefitinib and fulvestrant treatment alone, respectively. Antitumor effects of the combination therapy were accompanied by biochemical and histologic evidence of increased apoptosis, decreased phospho-p44/p42 mitogen-activated protein kinase expression, and increased Ki-67 expression compared with individual treatment. These studies provide evidence of a functional interaction between the ER and the EGFR pathways in NSCLC.

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“…Recent studies indicate that a second estrogen receptor, ERb, appears to play a role in nonsmall-cell carcinoma of the lung, whereas the classical estrogen receptor, ERa, is important breast and ovarian cancer. [37][38][39] Estrogen can directly stimulate the transcription of estrogen-responsive genes in the nucleus and cytoplasm of lung epithelial cells, thereby promoting downstream signaling resulting in hormone-mediated proliferation of lung tumors. 10,40 b-estradiol has been found to stimulate the growth of nonsmall cell tumor lines, and this effect was blocked by antiestrogens.…”

Section: Discussionmentioning

confidence: 99%

Reproductive and hormonal factors and risk of lung cancer in women: A prospective cohort study

Kabat

Miller

Rohan

2007

Intl Journal of Cancer

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Several lines of evidence suggest that endocrine factors may play a role in the development of lung cancer, but the evidence is limited and inconsistent. We investigated the association of reproductive and hormonal factors with risk of lung cancer in the National Breast Screening Study, which included 89,835 Canadian women aged 40-59 years at recruitment between 1980 and 1985. Linkages to national cancer and mortality databases provided data on cancer incidence and deaths from all causes, respectively, with follow-up ending between 1998 and 2000. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between hormonal factors and lung cancer. During a mean of 16.4 years of follow-up, we observed 750 incident lung cancer cases. After adjustment for covariates, parous women were not at increased risk of lung cancer (HR 5 1.18, 95% CI 0.94-1.47) relative to nulliparous women; however, there was a modest increase in risk with increasing parity, reaching a HR of 1.42, 95% CI 1.06-1.88 in women who had 5 or more live births (p for trend 0.02). Among parous women, age at first live birth was inversely associated with risk. Women who had their first live birth at age 30 or older were at reduced risk relative to women who had their first live birth below age 23 (HR 0.68, 95% CI 0.50-0.93, p for trend 0.004). These associations did not differ by age at enrollment (40-49 vs. 50-59 years old), but were somewhat strengthened when attention was restricted to never smokers. Ever use of exogenous hormones showed little association with lung cancer risk; however, long-term users of hormone replacement therapy were at slightly increased risk. Our results add to the limited existing evidence that certain reproductive and hormonal factors may be associated with lung cancer risk in women. ' 2007 Wiley-Liss, Inc.Key words: lung neoplasms; reproductive factors; menstrual factors; exogenous hormones Although cigarette smoking accounts for the vast majority of lung cancer incidence, several other factors that may contribute independently to lung cancer risk or modify the effects of smoking have been proposed. 1 Several lines of evidence suggest that endocrine factors may play a role in the development of lung cancer in women, but the evidence is limited and inconsistent. A greater proportion of female than male lung cancer cases occurs in never smokers, and lung cancer is more likely to be adenocarcinoma in women than in men. 2,3 Estrogen receptors and other steroid receptors have been detected in both normal lung tissue and lung tumors, but their significance and their role in lung cancer are unclear. 4-10 Additionally, some studies, though not all, suggest that women are more susceptible to tobacco carcinogenesis than men. 11-16 A small number of mostly case-control studies have examined the association of various reproductive and hormonal factors with lung cancer, but the results have been inconsistent. [17][18][19][20][21][22][23][24][25][26][27][28] Several...

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Expression, Function, and Clinical Implications of the Estrogen Receptor β in Human Lung Cancers

Cited by 181 publications

References 36 publications

The expression and function of estrogen receptor alpha and beta in human breast cancer and its clinical application.

The expression and function of estrogen receptor alpha and beta in human breast cancer and its clinical application.

Combined Targeting of the Estrogen Receptor and the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Shows Enhanced Antiproliferative Effects

Reproductive and hormonal factors and risk of lung cancer in women: A prospective cohort study

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