Cigarette Smoking and Estrogen-Related Cancer.

Collaborative analysis of case-control and cohort studies of breast cancer show that the hormone receptor positive phenotypes share much of the estrogenic risk factor profile seen in endometrial cancer: increased risks associated with early menarche, late menopause, low parity, and high post-menopausal BMI ( 70 - 73 ) ( Table 1 ). However, the effect of unopposed menopausal estrogens is not clear: observational studies have found users to have modestly increased risk ( 74 ), but the Women’s Health Initiative clinical trial found reduced risks ( 75 ) ( Table 1 ). In contrast to the other cancers considered here, cigarette smoking is not associated with a reduced risk of breast cancer. A pooled analysis of 14 cohort studies reported a small (7%) overall increase in risk among current smokers. There was a statistically significant interaction with alcohol drinking, with no increased risk among women who did not currently drink. Even the most estrogen-sensitive phenotypes, those that are ER positive or that have a luminal expression profile, do not display an inverse association with smoking: a pooled analysis of cohort studies reported a small increase in risk for ER positive breast cancer ( 76 ) and similar findings were reported for luminal phenotypes in population-based case-control studies ( 76 - 78 ). An interesting detail is that the relationship between smoking and breast cancer seems to differ depending on the ages when the smoking occurs. A pooled analysis of cohort studies documents that smoking initiation early in life has been consistently associated with a small increase in risk, particularly among women who started smoking before their first term birth ( 76 ). On the other hand, three large cohort studies found that the duration of post-menopausal smoking was inversely associated with risk while that for premenopausal smoking tended to increase risk ( 79 - 81 ). This mirrors the pattern observed for endometrial cancer, in which post-menopausal smoking – but not premenopausal smoking - is associated with reduced risks ( 7 , 8 ). Although smoking is not inversely associated with breast cancer risk, women who currently smoke have a lower radiographic breast density than former or never smokers (see, for example ( 82 , 83 )). A recent comprehensive study from a health insurance plan included over 23,0000 women and provides the most precise estimates ( 83 ). The lower breast density was seen in both premenopausal and postmenopausal current smokers, and was largely due to an increase in the non-dense breast area rather than a reduction in the dense areas.

The association of smoking with risk of thyroid cancer is also broadly similar to that for endometrial cancer: a meta-analysis ( 6 ) and a pooled analysis of cohort studies ( 43 ) found that current smokers (but not former smokers) have about a 25-30% lower risk than never smokers. This pattern is evident in women as well as in men ( 6 ). A combined analysis of cohort studies and the large Women’s Health Initiative cohort study document that the association remains after adjustment for alcohol intake and BMI (and for reproductive factors in women) ( 43 , 44 ). In addition, the combined cohort analyses reported that there is no apparent interaction of current smoking with age, sex, education, or BMI ( 43 ). The reduction in risk among current smokers is seen in both medullary and papillary thyroid cancer, though reductions in risk may be slightly larger for tumors with papillary histology (which comprise about 90% of thyroid cancers overall) ( 6 , 43 ), An estrogen dependence of thyroid cancer is clearly evident in rodent models and cell culture studies ( 45 , 46 ), and ERα is expressed in this malignancy ( 46 ). Nonetheless, the epidemiological characteristics of an estrogen dependence are relatively weak ( Table 1 ). Though incidence is higher among women than among men, mortality rates in the US are very similar ( 47 ). Meta-analysis and a pooled analysis of case-control studies show an increased risk among parous versus nulliparous women (though without a dose-response trend) ( 48 , 49 ) and there is a suggested increased risk with later age of menarche ( 48 , 50 ). Whether a late age of menopause is associated with an increased risk is not clear: a meta-analysis of cohort studies and the pooled case-control analysis ( 48 , 51 ) suggest that it is not, though two meta-analyses suggest that it is ( 52 , 53 ). In any case, the pooled analysis of case-control studies ( 48 ) and the Women’s Health Initiative cohort ( 54 ) show that women who have a surgical menopause have an increased risk. Meta-analysis ( 55 ) makes clear that thyroid cancer risk is positively associated with BMI in women. Studies that have assessed this in older or post-menopausal women in particular are generally consistent with a modest in increase in risk ( 56 - 62 ). Case-control ( 63 ) and cohort analyses ( 58 , 64 - 66 ) have not reported clear associations with unopposed menopausal estrogen therapy. Thus – at least epidemiologically -- thyroid cancer does not display the characteristics of an estrogen-sensitive malignancy. A complicating factor in thyroid cancer epidemiology is the overdiagnosis of subclinical lesions, which has led to a dramatic increase in recorded incidence over the past several decades ( 47 ). Thus, differential surveillance might play a role in the higher incidence in women. However, it is unlikely to underlie the inverse association with smoking: the utilization of outpatient care by current smokers has been variously observed to be less than ( 67 ), greater than ( 68 ), or about the same as that of non-smokers ( 69 ).

Although cigarette smoking is not associated with the overall risk of epithelial ovarian cancer ( 5 ), this is a heterogeneous malignancy, comprising different phenotypes with distinct molecular and clinical characteristics ( 32 ). Only mucinous cancers are derived from ovarian tissue itself. Serous tumors originate in the fallopian tubes, and endometrioid and clear cell ovarian cancers are thought to be derived from the endometrium, probably through retrograde menstruation. Recent combined analyses of individual level data from case-control and cohort studies have provided detailed risk factor data for ovarian cancer according to tumor histology. Endometrioid ovarian cancer has many of the same estrogenic risk factors as endometrial cancer: increasing risk with use of unopposed menopausal estrogens ( 33 ), lower parity and late age at menopause ( 34 ) ( Table 1 ). Higher BMI has also been associated with increased risks of endometrioid ovarian cancer in collaborative analyses and meta-analyses ( 34 - 36 ), though the association in postmenopausal women specifically is less clear in the few studies that have investigated it ( 37 , 38 ). Clear cell cancers share some estrogenic risk factors, but there is at most a weak association with BMI ( 34 - 36 ) (even among postmenopausal women ( 38 )) and no association or a reduced risk with use of unopposed estrogens ( Table 1 ) ( 33 , 39 ). ERα is commonly expressed in endometrioid ovarian cancers, but not in clear cell tumors ( 40 , 41 ). Collaborative analysis of case-control ( 5 , 42 ) and cohort studies ( 5 ) show that the associations of ovarian cancer with cigarette smoking differ according to the histology of the tumors. Smoking is not associated with serous ovarian cancer, and confers an increased risk of mucinous tumors. In contrast, the relationship of smoking with risk of endometrioid ovarian cancer resembles that for smoking and endometrial cancer. There is a reduction in risk of about 20% among current smokers that is attenuated in former smokers, and the associations are not confounded by factors such as BMI, use of hormone replacement therapy, oral contraceptive use, or reproductive history. There are no interactions of smoking status with BMI, alcohol use, parity, oral contraceptive use, menopausal hormone use, or family history of ovarian or breast cancer. Unlike endometrial cancer, the association with current smoking appears to be similar in pre- and post-menopausal women. Population-based case-control studies and cohort studies showed similar findings. There are less data available regarding smoking and clear cell ovarian cancer, but the inverse association for this malignancy is similar to that for endometrioid ovarian cancer.

Smoking is associated with several thyroid disorders, including an increased prevalence of goiter in iodine-deficient areas, and an increased risk of Graves hyperthyroidism ( 145 , 146 ). However, these findings would not explain an apparent protective effect of smoking on thyroid cancer. An anti-estrogenic effect of cigarette smoking has been proposed as an explanation, but the lack of epidemiological markers of estrogen responsiveness for thyroid cancer etiology reduces the plausibility of this argument. Chronic inflammation has a well-recognized carcinogenic impact ( 147 ) that may be relevant for thyroid cancer. Autoimmune (Hashimoto’s) thyroiditis is a chronic inflammation of the gland that has been associated with thyroid cancer in a series of cross-sectional studies (see, for example ( 148 - 150 )) and may also be inversely associated with smoking. In population surveys in Western countries ( 151 , 152 ), current smokers have a lower prevalence of the autoantibodies associated with autoimmune thyroiditis ( 151 , 152 ), though this association may depend on iodine status ( 152 , 153 ) and findings in Asia have been mixed (see e.g. ( 153 - 156 )). Data regarding the association of smoking with thyroiditis itself are conflicting. An early meta-analysis of two studies found increased risks in smokers ( 145 ). Subsequent investigations reported reduced risks ( 157 , 158 ) or null findings (for example, ( 159 - 161 )). Interpretation of all these studies is hampered by differences in criteria for autoimmune thyroiditis, and the fact that many of the investigations suffer from an ill-defined study base, investigation of prevalent cases, small sample sizes, and/or unadjusted analyses. Furthermore, evidence for an association between thyroiditis and thyroid cancer is largely derived from cross-sectional studies that were prone to selection biases in which high risk patients were more likely to be confirmed as cancer cases ( 148 , 162 ). Given these uncertainties, an anti-inflammatory effect of smoking is also not a convincing explanation for the inverse association of smoking with thyroid cancer. Another proposed explanation for a reduced risk of thyroid cancer in smokers is the lower levels of thyroid stimulating hormone (TSH, thyrotrophin) that has been documented in current smokers in population surveys (( 152 , 156 , 163 , 164 )). TSH is a growth factor for thyrocytes, and suppression of TSH secretion is used in the treatment of thyroid cancer ( 165 ). In cross-sectional studies of patients investigated for thyroid disease, those with thyroid cancer have higher TSH levels than those without ( 166 ), but in nested cohort analyses pre-diagnostic levels are not higher in future cases than in controls ( 167 , 168 ) and in a large Korean cohort study, adjustment for serum TSH only slightly attenuated the observed smoking association ( 169 ). TSH-supported proliferation may be needed for the progression of transformed cells, but TSH stimulation alone is not thought to lead to thyroid carcinogenesis ( 170 , 171 ). Thus, whether lower TSH levels explain the reduced thyroid cancer risk in smokers is uncertain.

The inverse associations between cigarette smoking and risk of endometrial cancer, endometrioid and clear cell ovarian cancers and thyroid cancer are reasonably well-documented. Studies of various designs in different populations have reported the findings, and confounding variables or obvious study biases do not readily explain the associations. The epidemiology is consistent with causal associations. In contrast, another estrogen-related cancer, breast cancer, does not display similar smoking associations. Although women who smoke cigarettes do not have lower circulating estrogen levels than non-smokers, the hormonal milieu within a tissue is likely to be more relevant for estrogen-related carcinogenesis. Inhibition of aromatase and the anti-estrogenic AhR effects detailed above clearly have the potential to interfere with local effects of estrogens. For endometrial cancer, this AhR interference with estrogen signaling is a plausible explanation for a causal protective effect of smoking. Inhibition of aromatase and consequent interference with local estrogen production seems less relevant, given the low aromatase expression in that malignancy, but a possible anti-inflammatory effect of smoking could support an anti-neoplastic effect ( Table 2 ). Inhibition of aromatase and AhR interference with estrogen signaling both seem relevant as explanations for the reduced risk of endometrioid ovarian cancer in smokers. But for clear cell ovarian cancer, the lack of expression of ERα and the weaker epidemiological suggestions of an estrogen dependence make estrogen-related mechanisms much less compelling ( Table 2 ). The possible anti-inflammatory effects of smoking could theoretically contribute to an anti-neoplastic effect of both endometrioid and clear cell ovarian cancers, but the lack of a clear association of smoking with endometriosis renders this uncertain. Proposed explanations for the inverse association of smoking with risk of thyroid cancer are also unsatisfactory ( Table 2 ). Since the epidemiology of this malignancy does not suggest a marked estrogen dependence, an anti-estrogenic effect of smoking is not a strong candidate. An anti-inflammatory impact of nicotine on thyroid cancer seems uncertain in light of the inconsistent data regarding the associations of smoking with thyroiditis and thyroiditis with thyroid cancer. Cigarette smoking does lower TSH levels, but it is not clear if that would be sufficient to lower risk of thyroid cancer. In summary, none of the proposed mechanisms for a protective effect of smoking on thyroid cancer risk are supported by compelling evidence ( Table 2 ). In contrast to the other estrogen-related cancers considered here, ER positive breast cancer is not inversely associated with cigarette smoking. Nonetheless, there are indications that post-menopausal smoking may temper any increased risks associated with premenopausal exposure. Together with the conflicting signals from preclinical studies, these findings suggest that smoking could have counterbalancing effects on breast carcinogenesis: a direct carcinogenic impact and a mitigating postmenopausal anti-estrogenic effect. It is conceivable that cigarette smoking could impede carcinogenesis through pathways other than interference with estrogen signaling, hormonal regulation, or inflammation. The AhR is a “promiscuous” receptor that can respond to a wide variety of environmental (and endogenous) compounds drawn from many classes of substances ( 172 ). Recent research has shown that the AhR is involved in a range of biological processes relevant to carcinogenesis: cell cycle progression, cell adhesion, proliferation, and immune response, for example ( 173 , 174 ). Often this enhances carcinogenesis, but sometimes it can be anti-neoplastic ( 175 , 176 ). The extent to which these mechanisms explain the inverse associations of cigarette smoking with the cancers considered here have not been studied in any detail. This reinforces an important point, that the effects of various AhR ligands and other constituents of cigarette smoke can differ. Moreover, AhR/ERα crosstalk is known to be context-dependent, varying across tissues with the expression of the AhR, ERα, ERβ, coactivators and suppressors of these receptors, and the various enzymes induced by the AhR ( 122 ). The fact that ERβ signaling often counteracts the effects of ERα ( 177 ) adds another element of complexity. ERβ is expressed in all the cancers discussed here ( 46 , 177 , 178 ), and may be particularly important for endometrioid and clear cell ovarian cancer because of its role in supporting the progression of endometriosis, which can evolve into these malignancies ( 94 , 179 ). High BMI is a risk factor for endometrial cancer, endometrioid and clear cell ovarian cancers and thyroid cancer, but the impact of smoking on these malignancies cannot be interpreted as an “anti-obesity” effect of some sort. As noted above, current smokers do tend to have a lower BMI than non-smokers. But they also tend to have an abdominal distribution of adipose tissue, as reflected in a higher waist-to-hip ratio ( 180 , 181 ). This confers many of the adverse consequences of high BMI itself – including increased risks of endometrial, postmenopausal breast and thyroid cancers ( 55 , 182 ); an increased risk of diabetes ( 183 ); and decreased circulating adiponectin levels ( 184 ). Although there are plausible mechanisms to explain smoking’s effect on endometrial cancer and endometrioid ovarian cancer, additional research will be required to more fully understand the inverse associations of smoking with clear cell ovarian cancer and thyroid cancer. Understanding what factors lead endometriosis to predispose to clear cell versus endometrioid ovarian cancer, with rather different estrogen associations, would contribute to the understanding of smoking’s association with the former. Clarification of the associations of thyroiditis with smoking on the one hand and thyroiditis with thyroid cancer on the other is needed to understand the role of inflammation in thyroid carcinogenesis and the impact of smoking on thyroid cancer incidence. Whatever the possible beneficial effects of smoking described here, the overall impact of cigarettes on health is undeniably extremely negative. The value of the unexpected protective associations discussed here is that they can provide clues to disease etiology, treatment and prevention, as has been the case for smoking’s associations with ulcerative colitis and Parkinson’s disease ( 185 ). The fact that smoking appears to exert an anti-estrogenic effect through AhR signaling suggests that this pathway would be a productive avenue for research regarding prevention or treatment for estrogen-related malignancies. Indeed, use of selective AhR ligands for treatment of breast cancer, and perhaps other malignancies, is an active line of research ( 122 ) and the AhR-active drug aminoflavone ( 186 , 187 ) has been in clinical trials for treatment of breast and other cancers.