Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Dana 517B, Boston, MA, 02215, USA.
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.
Breast Cancer Res Treat. 2019 Feb;173(3):667-677. doi: 10.1007/s10549-018-5034-1. Epub 2018 Nov 1.
In post-menopausal women, high body mass index (BMI) is an established breast cancer risk factor and is associated with worse breast cancer prognosis. We assessed the associations between BMI and gene expression of both breast tumor and adjacent tissue in estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) diseases to help elucidate the mechanisms linking obesity with breast cancer biology in 519 post-menopausal women from the Nurses' Health Study (NHS) and NHSII.
Differential gene expression was analyzed separately in ER+ and ER- disease both comparing overweight (BMI ≥ 25 to < 30) or obese (BMI ≥ 30) women to women with normal BMI (BMI < 25), and per 5 kg/m increase in BMI. Analyses controlled for age and year of diagnosis, physical activity, alcohol consumption, and hormone therapy use. Gene set enrichment analyses were performed and validated among a subset of post-menopausal cases in The Cancer Genome Atlas (for tumor) and Polish Breast Cancer Study (for tumor-adjacent).
No gene was differentially expressed by BMI (FDR < 0.05). BMI was significantly associated with increased cellular proliferation pathways, particularly in ER+ tumors, and increased inflammation pathways in ER- tumor and ER- tumor-adjacent tissues (FDR < 0.05). High BMI was associated with upregulation of genes involved in epithelial-mesenchymal transition in ER+ tumor-adjacent tissues.
This study provides insights into molecular mechanisms of BMI influencing post-menopausal breast cancer biology. Tumor and tumor-adjacent tissues provide independent information about potential mechanisms.
在绝经后妇女中，较高的体重指数（BMI）是已确立的乳腺癌危险因素，与乳腺癌预后较差相关。我们评估了 BMI 与雌激素受体阳性（ER+）和雌激素受体阴性（ER-）疾病的乳腺肿瘤和相邻组织基因表达之间的关联，以帮助阐明在来自护士健康研究（NHS）和 NHSII 的 519 名绝经后妇女中肥胖与乳腺癌生物学之间的联系的机制。
分别在 ER+和 ER-疾病中分析了差异基因表达，同时比较了超重（BMI≥25 至 <30）或肥胖（BMI≥30）妇女与正常 BMI（BMI<25）妇女之间，以及 BMI 每增加 5kg/m 时的差异。分析控制了年龄和诊断年份、身体活动、酒精摄入和激素治疗的使用。进行了基因集富集分析，并在癌症基因组图谱（用于肿瘤）和波兰乳腺癌研究（用于肿瘤相邻组织）中的绝经后病例亚集中进行了验证。
没有基因因 BMI 而表现出差异表达（FDR<0.05）。BMI 与细胞增殖途径的增加显著相关，特别是在 ER+肿瘤中，并且与 ER-肿瘤和 ER-肿瘤相邻组织中的炎症途径增加相关（FDR<0.05）。高 BMI 与 ER+肿瘤相邻组织中涉及上皮-间充质转化的基因上调相关。
本研究提供了关于 BMI 影响绝经后乳腺癌生物学的分子机制的见解。肿瘤和肿瘤相邻组织提供了潜在机制的独立信息。
