Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Clin Cancer Res. 2013 Sep 15;19(18):4972-4982. doi: 10.1158/1078-0432.CCR-13-0029. Epub 2013 Aug 5.
Previous studies of breast tissue gene expression have shown that the extratumoral microenvironment has substantial variability across individuals, some of which can be attributed to epidemiologic factors. To evaluate how mammographic density and breast tissue composition relate to extratumoral microenvironment gene expression, we used data on 121 patients with breast cancer from the population-based Polish Women's Breast Cancer Study.
Breast cancer cases were classified on the basis of a previously reported, biologically defined extratumoral gene expression signature with two subtypes: an Active subtype, which is associated with high expression of genes related to fibrosis and wound response, and an Inactive subtype, which has high expression of cellular adhesion genes. Mammographic density of the contralateral breast was assessed using pretreatment mammograms and a quantitative, reliable computer-assisted thresholding method. Breast tissue composition was evaluated on the basis of digital image analysis of tissue sections.
The Inactive extratumoral subtype was associated with significantly higher percentage mammographic density (PD) and dense area (DA) in univariate analysis (PD: P = 0.001; DA: P = 0.049) and in multivariable analyses adjusted for age and body mass index (PD: P = 0.004; DA: P = 0.049). Inactive/higher mammographic density tissue was characterized by a significantly higher percentage of stroma and a significantly lower percentage of adipose tissue, with no significant change in epithelial content. Analysis of published gene expression signatures suggested that Inactive/higher mammographic density tissue expressed increased estrogen response and decreased TGF-β signaling.
By linking novel molecular phenotypes with mammographic density, our results indicate that mammographic density reflects broad transcriptional changes, including changes in both epithelia- and stroma-derived signaling.
先前的乳腺组织基因表达研究表明，肿瘤外微环境在个体间具有很大的可变性，其中一些可归因于流行病学因素。为了评估乳腺密度和乳腺组织成分与肿瘤外微环境基因表达的关系，我们使用了基于人群的波兰女性乳腺癌研究中 121 例乳腺癌患者的数据。
根据先前报道的具有两种亚型的生物学定义的肿瘤外基因表达特征对乳腺癌病例进行分类：一种是活跃型，与纤维化和伤口反应相关基因的高表达相关；另一种是不活跃型，与细胞黏附基因的高表达相关。使用预处理乳房 X 光片和可靠的定量计算机辅助阈值方法评估对侧乳房的乳腺密度。根据组织切片的数字图像分析评估乳腺组织成分。
在单变量分析中，不活跃的肿瘤外亚型与显著较高的百分比乳腺密度（PD）和致密区域（DA）相关（PD：P=0.001；DA：P=0.049），并且在调整年龄和体重指数的多变量分析中也相关（PD：P=0.004；DA：P=0.049）。不活跃/更高的乳腺密度组织的特征是基质百分比显著较高，脂肪组织百分比显著较低，上皮含量没有显著变化。对已发表的基因表达特征的分析表明，不活跃/更高的乳腺密度组织表达了增加的雌激素反应和减少的 TGF-β信号。
通过将新的分子表型与乳腺密度联系起来，我们的结果表明，乳腺密度反映了广泛的转录变化，包括上皮和基质衍生信号的变化。
