Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, United States.
Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, United States.
Front Endocrinol (Lausanne). 2022 Jun 29;13:879164. doi: 10.3389/fendo.2022.879164. eCollection 2022.
The mechanisms underlying the association of overall and central body fatness with poorer breast cancer outcomes remain unclear; altered gene and/or protein expression of the adipokines and their receptors in breast tumors might play a role.
In a sample of Black and White women with primary invasive breast cancer, we investigated associations of body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), fat mass index (FMI), and percent body fat with protein expression (log-transformed, n = 722) and gene expression (log2-transformed, n = 148) of leptin (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), and adiponectin receptors 1 and 2 (ADIPOR1, ADIPOR2). Multivariable linear models, adjusting for race, menopausal status, and estrogen receptor status, were used to assess these associations, with Bonferroni correction for multiple comparisons.
In multivariable models, we found that increasing BMI (β = 0.0529, 95% CI: 0.0151, 0.0906) and FMI (β = 0.0832, 95% CI: 0.0268, 0.1397) were associated with higher gene expression, corresponding to 34.5% and 38.3% increases in gene expression for a standard deviation (SD) increase in BMI and FMI, respectively. Increasing BMI (β = 0.0028, 95% CI: 0.0011, 0.0045), waist circumference (β = 0.0013, 95% CI: 0.0005, 0.0022), hip circumference (β = 0.0015, 95% CI: 0.0007, 0.0024), and FMI (β = 0.0041, 95% CI: 0.0015, 0.0067) were associated with higher LEPR protein expression. These associations equate to 16.8%, 17.6%, 17.7%, 17.2% increases in LEPR protein expression for a 1-SD increase in BMI, waist circumference, hip circumference, and FMI, respectively. Further, these associations were stronger among White and postmenopausal women and ER+ cases; formal tests of interaction yielded evidence of effect modification by race. No associations of body fatness with LEP protein expression, gene expression, or protein or gene expression of ADIPOQ, ADIPOR1, and ADIPOR2 were found.
These findings support an association of increased body fatness - beyond overall body size measured using BMI - with higher gene expression and higher LEPR protein expression in breast tumor tissues. Clarifying the impact of adiposity-related adipokine and adipokine receptor expression in breast tumors on long-term breast cancer outcomes is a critical next step.
全身和中心体脂肪与乳腺癌不良预后之间的关联机制尚不清楚；脂肪因子及其受体在乳腺肿瘤中的基因和/或蛋白表达的改变可能发挥作用。
在一组患有原发性浸润性乳腺癌的黑人和白人女性中，我们研究了体重指数（BMI）、腰围、臀围、腰臀比（WHR）、脂肪量指数（FMI）和体脂百分比与瘦素（LEP）、瘦素受体（LEPR）、脂联素（ADIPOQ）和脂联素受体 1 和 2（ADIPOR1、ADIPOR2）的蛋白表达（对数转换，n = 722）和基因表达（log2 转换，n = 148）的关联。使用多变量线性模型，调整种族、绝经状态和雌激素受体状态，评估这些关联，并使用 Bonferroni 校正进行多重比较。
在多变量模型中，我们发现 BMI（β = 0.0529，95%CI：0.0151，0.0906）和 FMI（β = 0.0832，95%CI：0.0268，0.1397）的增加与基因表达增加相关，分别对应于 BMI 和 FMI 的标准偏差（SD）增加 34.5%和 38.3%的基因表达增加。BMI（β = 0.0028，95%CI：0.0011，0.0045）、腰围（β = 0.0013，95%CI：0.0005，0.0022）、臀围（β = 0.0015，95%CI：0.0007，0.0024）和 FMI（β = 0.0041，95%CI：0.0015，0.0067）的增加与 LEPR 蛋白表达增加相关。这些关联相当于 BMI、腰围、臀围和 FMI 的 SD 增加 1 时，LEPR 蛋白表达分别增加 16.8%、17.6%、17.7%和 17.2%。此外，这些关联在白人女性和绝经后女性以及 ER+病例中更强；对交互作用的正式检验表明，种族存在效应修饰的证据。未发现体脂与 LEP 蛋白表达、基因表达或 ADIPOQ、ADIPOR1 和 ADIPOR2 的蛋白或基因表达之间存在关联。
这些发现支持全身脂肪增加（BMI 以外的整体身体大小）与乳腺肿瘤组织中基因表达增加和 LEPR 蛋白表达增加之间的关联。阐明与肥胖相关的脂肪因子及其受体在乳腺肿瘤中的表达对长期乳腺癌结局的影响是下一步的关键。
