Budesonide exerts its chemopreventive efficacy during mouse lung tumorigenesis by modulating gene expressions

Yao, Ruisheng; Wang, Yian; Lemon, William J.; Lubet, Ronald A.; You, Ming

doi:10.1038/sj.onc.1207985

Cited by 47 publications

(42 citation statements)

References 20 publications

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“…Furthermore, in some tissues including skin, glucocorticoids act as potent tumor suppressors (Schwartz et al, 1977;Verma et al, 1983;Yao et al, 2004). We found that the expression of GR is decreased in experimentally induced skin tumors in SENCAR mice especially during the early stages of skin carcinogenesis (Budunova et al, 1997).…”

Section: Discussionmentioning

confidence: 78%

The tumor suppressor effect of the glucocorticoid receptor in skin is mediated via its effect on follicular epithelial stem cells

et al. 2006

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Glucocorticoids are potent inhibitors of mouse skin tumorigenesis. The glucocorticoid control of cellular functions is mediated via the glucocorticoid receptor (GR), a well-known transcription factor. Recently, we generated transgenic mice overexpressing GR under control of the keratin5 (K5) promoter, and showed that K5.GR animals are resistant to skin carcinogenesis. Follicular epithelial stem cells (SCs), located in the bulge region of the hair follicle, are believed to be one of the target cells for skin carcinogenesis. We found that the number of putative hair follicle SC detected as labelretaining cells was significantly less in the K5.GR transgenics compared to wild type (w.t.) littermates. We also showed that GR overexpression led to a reduction in the clonogenicity of the follicular epithelial SCs. We evaluated the global effect of GR on gene expression in a population of follicular SC-enriched bulge keratinocytes isolated by fluorescence activated cell sorting. We found that GR affected the expression of numerous bulge SC 'signature' genes, genes involved in the maintenance of SC and progenitor cells of non-epidermal origin and proapoptotic genes. Our findings underscore the important role of GR signaling in the homeostasis of follicular epithelial SCs, and suggest that the reduction in their number may underlie the tumor suppressor effect of GR in the skin.

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Section: Discussionmentioning

confidence: 78%

The tumor suppressor effect of the glucocorticoid receptor in skin is mediated via its effect on follicular epithelial stem cells

et al. 2006

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“…One of the difficulties in evaluating the efficacy of a chemopreventive agent is the lack of biomarkers that could ultimately be assessed not only in the animal model but also in human clinical trials. Although most chemopreventives act by affecting multiple signaling pathways to cause growth arrest and/or apoptosis, we and others have asked whether agents that cause the reexpression of tumor suppressor genes silenced by methylation could be an effective approach for reversing preinvasive disease or blocking cancer progression (5). Silencing of genes by promoter hypermethylation is now recognized as a crucial component in lung cancer initiation and progression, making it an attractive target for prevention (6,7).…”

Section: Introductionmentioning

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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“…Budesonide is a glucocorticoid, a family of compounds that are effective cancer chemopreventive agents in animal models but can have side effects in humans (24). Several studies showed that budesonide, given either in diet or by aerosol, inhibits the formation of lung tumors in the lung of mice treated either with benzo(a)pyrene (24)(25)(26)(27)(28)(29)(30) or vinyl carbamate (31). In addition, budesonide was found to modulate gene expression during mouse lung tumorigenesis (28).…”

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confidence: 99%

“…Several studies showed that budesonide, given either in diet or by aerosol, inhibits the formation of lung tumors in the lung of mice treated either with benzo(a)pyrene (24)(25)(26)(27)(28)(29)(30) or vinyl carbamate (31). In addition, budesonide was found to modulate gene expression during mouse lung tumorigenesis (28). PEITC is a naturally occurring isothiocyanate contained in watercress (Nasturtium officinale), which has been shown to inhibit lung tumors induced in mice and rats by NNK (32)(33)(34)(35)(36), whose metabolic activation is blocked by PEITC (34).…”

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confidence: 99%

Modulation by Phenethyl Isothiocyanate and Budesonide of Molecular and Histopathologic Alterations Induced by Environmental Cigarette Smoke in Mice

D’Agostini

Mastracci

Izzotti

et al. 2009

Cancer Prevention Research

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Our discovery that the perinatal period involves nucleotide modifications and gene overexpression in mouse lung prompted us to evaluate whether mice may become more susceptible to cigarette smoke when exposure starts immediately after birth. We previously showed that mainstream cigarette smoke is a quite potent carcinogen in neonatal mice. Further on, we showed that exposure of mice to environmental cigarette smoke (ECS), starting at birth, results in alterations of a variety of intermediate biomarkers. However, after 4 months of exposure to ECS followed by 7 months of recovery in filtered air, the lung tumor yield was rather low. In the present study, we evaluated the protective effects of the glucocorticoid budesonide and of the dietary agent phenethyl isothiocyanate in mice exposed to ECS for 9 months followed by 2 months of recovery. After weanling, the mice exposed to ECS since birth underwent a variety of alterations of molecular and cytogenetical end points, and 11 months after birth, they exhibited significant histopathologic changes, such as pulmonary anthracosis, emphysema, hemorrhagic areas, alveolar bronchiolarization, bronchial hyperplasia, and tumors, both benign and malignant. The carcinogenic response was less evident in dams exposed to ECS under identical conditions. Both phenethyl isothiocyanate and budesonide, administered daily with the diet after weanling, attenuated several alterations of ECS-related biomarkers and moderately protected the lungs from histopathologic alterations, including tumors. Thus, although not as efficiently as the bioassay in mainstream cigarette smoke-exposed mice, the model in neonatal mice is suitable to evaluate both ECS carcinogenicity and its modulation by chemopreventive agents.

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Budesonide exerts its chemopreventive efficacy during mouse lung tumorigenesis by modulating gene expressions

Cited by 47 publications

References 20 publications

The tumor suppressor effect of the glucocorticoid receptor in skin is mediated via its effect on follicular epithelial stem cells

The tumor suppressor effect of the glucocorticoid receptor in skin is mediated via its effect on follicular epithelial stem cells

Gene Promoter Hypermethylation in Mouse Lung Tumors

Modulation by Phenethyl Isothiocyanate and Budesonide of Molecular and Histopathologic Alterations Induced by Environmental Cigarette Smoke in Mice

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