Prometastatic Molecular Profiles in Breast Tumors From Socially Isolated Women.
Prometastatic Molecular Profiles in Breast Tumors From Socially Isolated Women.
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DOI：
10.1093/jncics/pky029
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发表时间：
2018-07
影响因子：
4.4
通讯作者：
Cole SW
中科院分区：
文献类型：
--
作者：
Bower JE;Shiao SL;Sullivan P;Lamkin DM;Atienza R;Mercado F;Arevalo J;Asher A;Ganz PA;Cole SW
社交孤立与乳腺癌进展加速、疾病复发率和死亡率增加有关，但其潜在的生物学机制仍知之甚少。在临床前模型中，来自战或逃应激反应的β-肾上腺素能信号传导可以刺激肿瘤微环境中的促转移过程，包括M2巨噬细胞的上调、上皮-间质转化（EMT）和淋巴血管侵袭。这项研究检查了是否相同的途径在社会孤立的癌症患者的乳腺肿瘤中上调。通过全基因组转录谱分析EMT和M1/M2巨噬细胞基因表达程序，并通过免疫组织化学评估来自56名早期乳腺癌患者的原发性肿瘤中的淋巴管和血管密度，这些患者是UCLA RISE研究的一部分。通过社会供给量表量化社会隔离，通过病历审查评估疾病特征。一般线性模型用于量化风险因素组之间的差异基因表达。线性回归模型被用来研究社会隔离和淋巴管浸润之间的关系。来自社会隔离患者的肿瘤显示参与EMT的基因表达上调（平均得分差异= +0.080 log 2 mRNA丰度± 0.034标准误差）和M2巨噬细胞极化（+0.033 ± 0.014）以及淋巴管密度增加（β=-0.29），但血管密度无差异。基于TELiS启动子的生物信息学分析表明CREB家族转录因子的激活，其介导β-肾上腺素能信号传导的基因调节作用（启动子结合位点流行率的log 2倍数差异：平均值±标准误差= +0.49 ± 0.19）。 来自社会孤立患者的原发性乳腺肿瘤显示出多种促转移分子改变，提供了一个合理的生物学途径，通过该途径，不良的社会支持可能加速乳腺癌进展，并确定了新的干预靶点。
Social isolation is associated with accelerated breast cancer progression and increased disease recurrence and mortality, but the underlying biological mechanisms remain poorly understood. In preclinical models, beta-adrenergic signaling from fight-or-flight stress responses can stimulate prometastatic processes in the tumor microenvironment including upregulation of M2 macrophages, epithelial–mesenchymal transition (EMT), and lymphovascular invasion. This study examines whether the same pathways are upregulated in breast tumors from socially isolated cancer patients. EMT and M1/M2 macrophage gene expression programs were analyzed by genome-wide transcriptional profiling, and lymphatic and vascular density were assessed by immunohistochemistry in primary tumors from 56 early-stage breast cancer patients who were part of the UCLA RISE study. Social isolation was quantified by the Social Provisions Scale, and disease characteristics were assessed by medical record review. General linear models were used to quantify differential gene expression across risk factor groups. Linear regression models were used to examine associations between social isolation and lymphovascular invasion. Tumors from socially isolated patients showed upregulated expression of genes involved in EMT (average score difference = +0.080 log2 mRNA abundance ± 0.034 standard error) and M2 macrophage polarization (+0.033 ± 0.014) as well as increased density of lymphatic vessels (β= –.29) but no difference in blood vessel density. TELiS promoter–based bioinformatics analyses indicated activation of CREB family transcription factors that mediate the gene-regulatory effects of β-adrenergic signaling (log2 fold-difference in promoter binding site prevalence: mean ± standard error = +0.49 ± 0.19). Primary breast tumors from socially isolated patients show multiple prometastatic molecular alterations, providing a plausible biological pathway through which poor social support may accelerate breast cancer progression and defining new targets for intervention.