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Protective Effects of Estrogen in a Genetically Defined Mouse Model of Lung Adenocarcinoma

ABSTRACT: The role of reproductive hormones in lung cancer is controversial; obervations from epidemiological studies support the possibilities that estrogen either promotes or protects against the disease. In an earlier study we reported that estradiol (E2) stimulated tumorigenesis in a genetically defined mouse model based on the conditional expression of oncogenic Kras and concomitant deletion of p53. The present study was meant to further examine the effects of estrogens in this model. Instead we found that tumorigenesis was inhibited by the presence of the ovaries and that E2 proved protective against tumorigenesis in ovariectomized animals. Specifically, E2 and the Esr1-specific agonist PPT reduced the number and size of tumors that developed; furthermore, the protective effects of these two steroids were dose-dependent. However, the Esr2 agonist DPN produced no effect. Since Esr2 predominates in the lung, these results suggest that the E2 effect is indirect, perhaps being mediated by an endocrine factor from another organ. Furthermore, the fact that the E2 effect in this second iteration of the mouse model was diametrically opposed to our earlier results suggests that genetic background plays a critical role in determining the effect of estrogen.

ORGANISM(S): Mus musculus

PROVIDER: GSE61837 | GEO | 2015/09/25

SECONDARY ACCESSION(S): PRJNA262517

REPOSITORIES: GEO

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Project description:E2 exposure significantly decreased peak viral titer in hNECs from female donors. We used microarray analyses to identify global gene expression patterns between E2 and vehicle exposed hNECs from female donors Influenza causes an acute infection characterized by virus replication in respiratory epithelial cells. The severity of influenza and other respiratory diseases changes over the life course and during pregnancy in women, suggesting that sex steroid hormones, such as estrogens, may be involved. Using primary, differentiated human nasal epithelial cell (hNEC) cultures from adult male and female donors, we exposed cultures to the endogenous 17Î²-estradiol (E2) or select estrogen receptor modulators (SERMs), then infected cultures with a seasonal influenza A virus (IAV) to determine whether estrogenic signaling could affect the outcome of IAV infection and whether these effects where sex-dependent. Estradiol, raloxifene, and bisphenol A decreased IAV titers in hNECs from female, but not male, donors. The estrogenic decrease in viral titer was dependent on the genomic estrogen receptor- 2 (ESR2) as neither genomic ESR1 nor non- genomic GPR30 were expressed in hNEC cultures and addition of the genomic ER antagonist ICI 182,780 reversed the antiviral effects of E2. Treatment of hNECs with E2 had no effect on interferon or chemokine secretion, but significantly downregulated cell metabolic processes, including genes that encode for zinc finger proteins, many of which contain estrogen response elements in their promoters. These data provide novel insights into the cellular and molecular mechanisms of how natural and synthetic estrogens impact IAV infection in respiratory epithelial cells derived from humans. Primary human nasal epithelial cells from females were exposed to E2 for 24h prior to infection, then infected with an H3N2 strain of influenza a virus for 2 hours. At 24 and 48h post infection, hNECs were collected in Trizol for RNA extraction and hybridization on Affymetrix Human Gene ST 2.0 microarrays.

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Protective Effects of Estrogen in a Genetically Defined Mouse Model of Lung Adenocarcinoma

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