Cigarette smoking is a known cause of many cancers, yet epidemiological studies have found protective associations with the risk of four “estrogen-related” malignancies: endometrial cancer, endometrioid and clear cell ovarian cancers, and thyroid cancer. This review considers epidemiological and biological aspects of these associations, focusing particularly on estrogen signaling, and contrasts them with those for breast cancer, another estrogen-related malignancy. The observational findings regarding the inverse associations are consistent and remain after adjustment for possible confounding factors. In general, women who smoke do not have lower circulating estrogen levels than non-smokers, eliminating one possible explanation for reduced risks of these malignancies. For endometrial and endometrioid ovarian cancer, the negative associations could plausibly be explained by interference with signaling through the estrogen receptor alpha. However, this is unlikely to explain the lower risks of thyroid and clear cell ovarian cancers. For thyroid cancer, an anti-inflammatory effect of nicotine and reduced TSH levels from smoking have been proposed explanations for the inverse association, but both lack convincing evidence. While the overall impact of cigarette smoking is overwhelmingly negative, protective associations such as those discussed here can provide potential clues to disease etiology, treatment and prevention.
Copyright ©2021, American Association for Cancer Research.

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