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

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.

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