Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
J Natl Cancer Inst. 2021 Jun 1;113(6):778-784. doi: 10.1093/jnci/djaa169.
Cumulative epidemiologic evidence has shown that early-life adiposity is strongly inversely associated with breast cancer risk throughout life, independent of adult obesity. However, the molecular mechanisms remain poorly understood.
We assessed the association of early-life adiposity, defined as self-reported body size during ages 10-20 years from a validated 9-level pictogram, with the transcriptome of breast tumor (N = 835) and tumor-adjacent histologically normal tissue (N = 663) in the Nurses' Health Study. We conducted multivariable linear regression analysis to identify differentially expressed genes in tumor and tumor-adjacent tissue, respectively. Molecular pathway analysis using Hallmark gene sets (N = 50) was further performed to gain biological insights. Analysis was stratified by tumor estrogen receptor (ER) protein expression status (n = 673 for ER+ and 162 for ER- tumors).
No gene was statistically significantly differentially expressed by early-life body size after multiple comparison adjustment. However, pathway analysis revealed several statistically significantly (false discovery rate < 0.05) upregulated or downregulated gene sets. In stratified analyses by tumor ER status, larger body size during ages 10-20 years was associated with decreased cellular proliferation pathways, including MYC target genes, in both ER+ and ER- tumors. In ER+ tumors, larger body size was also associated with upregulation in genes involved in TNFα/NFkB signaling. In ER- tumors, larger body size was additionally associated with downregulation in genes involved in interferon α and interferon γ immune response and Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling; the INFγ response pathway was also downregulated in ER- tumor-adjacent tissue, though at borderline statistical significance (false discovery rate = 0.1).
These findings provide new insights into the biological and pathological underpinnings of the early-life adiposity and breast cancer association.
累积的流行病学证据表明，在整个生命周期中，早期肥胖与乳腺癌风险呈强烈负相关，与成年肥胖无关。然而，其分子机制仍知之甚少。
我们评估了早发肥胖的相关性，早发肥胖的定义为通过验证的 9 级图像自报 10-20 岁期间的体型，并与护士健康研究中乳腺癌肿瘤（N=835）和肿瘤相邻组织学正常组织（N=663）的转录组相关联。我们分别进行多变量线性回归分析以识别肿瘤和肿瘤相邻组织中差异表达的基因。使用 Hallmark 基因集（N=50）进行的分子途径分析进一步提供了生物学见解。分析按肿瘤雌激素受体（ER）蛋白表达状态（n=673 例 ER+肿瘤和 162 例 ER-肿瘤）分层进行。
经多次比较调整后，早期体型没有统计学意义上的差异表达基因。然而，途径分析显示了几个统计学上显著（错误发现率<0.05）上调或下调的基因集。根据肿瘤 ER 状态的分层分析，10-20 岁期间较大的体型与 ER+和 ER-肿瘤中细胞增殖途径的减少有关，包括 MYC 靶基因。在 ER+肿瘤中，较大的体型还与 TNFα/NFkB 信号转导相关的基因上调有关。在 ER-肿瘤中，较大的体型还与干扰素α和干扰素γ免疫反应以及磷脂酰肌醇 3-激酶（PI3K）/AKT/雷帕霉素（mTOR）信号通路相关的基因下调有关；干扰素γ反应途径在 ER-肿瘤相邻组织中也下调，尽管处于边缘统计学意义（错误发现率=0.1）。
这些发现为早期肥胖与乳腺癌相关性的生物学和病理基础提供了新的见解。
