细颗粒物暴露与乳腺肿瘤和相邻正常乳腺组织中基因表达途径的关系。
Involvement of fine particulate matter exposure with gene expression pathways in breast tumor and adjacent-normal breast tissue.
机构信息
Channing Division of Network Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology and Population Health, University of Louisville School of Public Health and Information Sciences, Louisville, KY, USA.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA.
出版信息
Environ Res. 2020 Jul;186:109535. doi: 10.1016/j.envres.2020.109535. Epub 2020 Apr 15.
BACKGROUND
Fine particulate matter (PM) has been associated with breast cancer specific mortality, particularly for women with Stage I cancer. We examined the biological pathways that are perturbed by PM exposures by analyzing gene expression measurements from breast tissue specimens.
METHODS
The Nurses' Health Studies (NHS and NHSII) are prospective cohorts with archival breast tissue specimens from breast cancer cases. Global gene expression data were ascertained with the Affymetrix Glue Human Transcriptome Array 3.0. PM was estimated using spatio-temporal models linked to participants' home addresses. All analyses were performed separately in tumor (n = 591) and adjacent-normal (n = 497) samples, and stratified by estrogen receptor (ER) status and stage. We used multivariable linear regression, gene-set enrichment analyses (GSEA), and the least squares kernel machine (LSKM) to assess whether 3-year cumulative average pre-diagnosis PM exposure was associated with breast-tissue gene expression pathways among predominately Stage I and II women (90.7%) and postmenopausal (81.2%) women. Replication samples (tumor, n = 245; adjacent-normal, n = 165) were measured on Affymetrix Human Transcriptome Array (HTA 2.0).
RESULTS
Overall, no pathways in the tumor area were significantly associated with PM exposure. Among 272 adjacent-normal samples from Stage I ER-positive women, PM was associated with perturbations in the oxidative phosphorylation, protein secretion, and mTORC1 signaling pathways (GSEA and LSKM p-values <0.05); however, results were not replicated in a small set of replication samples (n = 80).
CONCLUSIONS
PM was generally not associated with breast tissue gene expression though was suggested to perturb oxidative phosphorylation and regulation of proteins and cellular signaling in adjacent-normal breast tissue. More research is needed on the biological role of PM that influences breast tumor progression.
背景
细颗粒物（PM）与乳腺癌特异性死亡率有关，特别是对于患有 I 期癌症的女性。我们通过分析乳腺癌组织标本的基因表达测量值来研究 PM 暴露干扰的生物学途径。
方法
护士健康研究（NHS 和 NHSII）是前瞻性队列研究，有乳腺癌病例的存档乳腺癌组织标本。通过 Affymetrix Glue Human Transcriptome Array 3.0 获得全球基因表达数据。使用与参与者家庭住址相关的时空模型来估计 PM。所有分析均分别在肿瘤（n=591）和相邻正常组织（n=497）样本中进行，并按雌激素受体（ER）状态和分期分层。我们使用多变量线性回归、基因集富集分析（GSEA）和最小二乘核机器（LSKM）来评估 3 年累积平均诊断前 PM 暴露是否与主要为 I 期和 II 期（90.7%）和绝经后（81.2%）女性的乳腺组织基因表达途径相关。复制样本（肿瘤，n=245；相邻正常，n=165）在 Affymetrix Human Transcriptome Array（HTA 2.0）上进行测量。
结果
总体而言，肿瘤区域没有任何途径与 PM 暴露显著相关。在 272 名 I 期 ER 阳性女性的相邻正常样本中，PM 与氧化磷酸化、蛋白质分泌和 mTORC1 信号通路的扰动相关（GSEA 和 LSKM p 值<0.05）；然而，在一小部分复制样本（n=80）中未得到验证。
结论
PM 通常与乳腺组织基因表达无关，但据报道，PM 会干扰相邻正常乳腺组织中的氧化磷酸化和蛋白质及细胞信号的调节。需要进一步研究 PM 对影响乳腺肿瘤进展的生物学作用。
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