Quigley David A, Tahiri Andliena, Lüders Torben, Riis Margit H, Balmain Allan, Børresen-Dale Anne-Lise, Bukholm Ida, Kristensen Vessela
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Oncoimmunology. 2017 Aug 10;6(11):e1356142. doi: 10.1080/2162402X.2017.1356142. eCollection 2017.
Chronic inflammation promotes breast tumor growth and invasion by accelerating angiogenesis and tissue remodeling in the tumor microenvironment. There is a complex relationship between inflammation and estrogen, which drives the growth of 70 percent of breast tumors. While low levels of estrogen exposure stimulate macrophages and other inflammatory cell populations, very high levels are immune suppressive. Breast tumor incidence is increased by obesity and age, which interact to influence inflammatory cell populations in normal breast tissue. To characterize the impact of these factors on tumors and the tumor microenvironment, we measured gene expression in 195 breast adenocarcinomas and matched adjacent normal breast tissue samples collected at Akershus University Hospital (AHUS). Age and Body Mass Index (BMI) were independently associated with inflammation in adjacent normal tissue but not tumors. Estrogen Receptor (ER)-negative tumors had elevated macrophage expression compared with matched normal tissue, but ER-positive tumors showed an unexpected decrease in macrophage expression. We found an inverse relationship between the increase in tumor estrogen pathway expression compared with adjacent normal tissue and tumor macrophage score. We validated this finding in 126 breast tumor-normal pairs from the previously published METABRIC cohort. We developed a novel statistic, the Rewiring Coefficient, to quantify the rewiring of gene co-expression networks at the level of individual genes. Differential correlation analysis demonstrated distinct pathways were rewired during tumorigenesis. Our data support an immune suppressive effect of high doses of estrogen signaling in breast tumor microenvironment, suggesting that this effect contributes to the greater presence of prognostic and therapeutically relevant immune cells in ER-negative tumors.
慢性炎症通过加速肿瘤微环境中的血管生成和组织重塑来促进乳腺肿瘤的生长和侵袭。炎症与雌激素之间存在复杂的关系，雌激素驱动着70%的乳腺肿瘤生长。低水平的雌激素暴露会刺激巨噬细胞和其他炎症细胞群体，而高水平的雌激素则具有免疫抑制作用。肥胖和年龄会增加乳腺肿瘤的发病率，它们相互作用影响正常乳腺组织中的炎症细胞群体。为了表征这些因素对肿瘤和肿瘤微环境的影响，我们在阿克什胡斯大学医院（AHUS）收集的195例乳腺腺癌及匹配的相邻正常乳腺组织样本中测量了基因表达。年龄和体重指数（BMI）与相邻正常组织中的炎症独立相关，但与肿瘤无关。与匹配的正常组织相比，雌激素受体（ER）阴性肿瘤的巨噬细胞表达升高，但ER阳性肿瘤的巨噬细胞表达却意外下降。我们发现，与相邻正常组织相比，肿瘤雌激素途径表达的增加与肿瘤巨噬细胞评分呈负相关。我们在先前发表的METABRIC队列中的126对乳腺肿瘤-正常组织样本中验证了这一发现。我们开发了一种新的统计量——重连系数，以量化单个基因水平上基因共表达网络的重连情况。差异相关性分析表明，在肿瘤发生过程中不同的途径发生了重连。我们的数据支持高剂量雌激素信号在乳腺肿瘤微环境中的免疫抑制作用，这表明这种作用导致了ER阴性肿瘤中预后和治疗相关免疫细胞的大量存在。
