In this study including 330 cases of primarily premenopausal breast cancer, we observed a borderline significant inverse association between plasma leptin levels in the highest quartile and breast cancer risk. However, after adjustment for concurrent BMI, the association was no longer statistically significant.
Consistent with our results, in two retrospective case-control studies inverse associations between leptin levels and premenopausal breast cancer risk were also observed. Petrido et al., reported an odds ratio of 0.1 (95% CI 0.0–0.9) for one standard deviation change in serum leptin level comparing 14 cases to 15 controls and Falk et al., reported an odds ratio for the highest vs. lowest quartile leptin of 0.71 (95% CI 0.5–1.3) with 233 cases and 251 controls.(23
) Conversely, another case-control study reported a significant positive association between plasma leptin levels and premenopausal breast cancer but did not adjust for any covariates.(31
) Five other retrospective case-control studies have reported non-significant positive associations between leptin levels and premenopausal breast cancer risk(26
) and one case-control study reported no association with premenopausal breast cancer.(30
) These conflicting results may partly be explained by the measurement of leptin post diagnosis, small sample sizes, varying level of control for confounders, differences in sample collection and measurement techniques, and heterogeneity of associations with pre- and postmenopausal breast cancer.
Leptin can promote estrogen production,(20
) or conversely, may limit follicular estradiol secretion,(23
) and thus, as is hypothesized for BMI, may influence breast cancer risk through hormonal pathways. However, it is very difficult to separate the independent effects of BMI and leptin due to their close biological relation. Leptin levels may change with adiposity since, as part of a negative feedback loop, leptin reduces appetite and increases the metabolic rate. Due to this circular relation between BMI and leptin, BMI may be a confounder or may be on the biological pathway of the leptin-premenopausal breast cancer relation and possibly approximately collinear with plasma leptin levels. We therefore presented our covariate-adjusted analyses in various ways: without adjustment for body size, with adjustment for BMI at age 18 and weight change from age 18 to blood draw (which is synonymous to BMI at blood draw but avoids collinearity with leptin concentrations since BMI at age 18 is less strongly correlated with plasma leptin levels than BMI at blood draw), and with adjustment for BMI at blood draw. In addition, to examine a measure of leptin uncorrelated with BMI, we used the residual method(40
) which allows for more complete control of the strong confounding by BMI and avoids collinearity. We observed a non-significant inverse association between the highest quartile of BMI-adjusted residuals of leptin and breast cancer risk. This suggests that leptin’s association with breast risk is at least partially mediated through BMI.
Leptin has been reported to enhance aromatase activity in MCF-7 cell lines,(41
) which may enhance estrogen production and induce tumor cell growth.(42
) Similarly, leptin receptors are expressed in T47-D breast cancer cell lines and leptin induces proliferation of T47-D cells.(15
) However, leptin may also reduce breast cancer risk through other mechanisms. Leptin is involved in the regulation of ovarian folliculogenesis(22
) and at high levels may reduce follicular estradiol secretion.(23
) In addition, obese leptin receptor-deficient mice have a decreased incidence of mammary tumors,(10
) thus an individual with elevated leptin levels could be at a reduced risk for breast cancer due to leptin resistance(43
) and its association with reduced leptin receptor activity.(45
) Moreover, the soluble leptin receptor (sOB-R), which may play an important role in the availability of circulating leptin,(46
) has been more strongly associated with risk of diseases such as diabetes(47
) and PCOS(48
) than plasma leptin.
A limitation of our study was that we only had a single plasma leptin measurement which may not accurately capture an individual’s true long-term average level of leptin. However, the intraclass correlations reported for leptin over a one to four year period are high, ranging from 0.74 to 0.82.(34
) Another limitation is the potential for misclassification due to laboratory error (CV 14%), but differential misclassification was unlikely due to the blinding of lab personnel to case status and to assaying cases and controls in the same batch. Potential misclassification of leptin measurements are therefore most likely non-differential with respect to breast cancer and would thus have attenuated our results.
Circulating hormones associated with both leptin and premenopausal breast cancer may confound the association.(18
) We were able to adjust for several hormones including insulin, adiponectin, IGF-1, IGFBP-3, and estradiol in this analysis, and minimally changed the leptin association. Residual confounding by these biomarkers may remain, due to random measurement error. BMI at age 18 and BMI at blood draw may have been affected by measurement error, however the validity of these measures has been reported to range from 0.84 to 0.99.(50
) Residual confounding is likely to have attenuated any observed associations.
To our knowledge, this is the first study to examine the relation between leptin and primarily premenopausal breast cancer risk using blood samples collected prior to cancer diagnosis. We also have high follow-up rates, cancer cases that have been confirmed by medical records, and data on many important covariates, including BMI at blood draw and at age 18, other hormones, and other risk factors for breast cancer.
In conclusion, our data do not support an increase in the risk of breast cancer with high leptin levels. Our results suggest that leptin may be inversely associated with breast cancer risk, but it is unclear whether any part of this association is independent of BMI. Future studies that examine the association between premenopausal breast cancer risk and leptin receptor levels which are more strongly related with risk of diabetes and PCOS than plasma leptin concentrations may further our understanding of this relation.