Piccolo Stephen R, Hoffman Laura M, Conner Thomas, Shrestha Gajendra, Cohen Adam L, Marks Jeffrey R, Neumayer Leigh A, Agarwal Cori A, Beckerle Mary C, Andrulis Irene L, Spira Avrum E, Moos Philip J, Buys Saundra S, Johnson William Evan, Bild Andrea H
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA Division of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA Department of Biology, Brigham Young University, Provo, UT, USA.
Huntsman Cancer Institute, Salt Lake City, UT, USA Department of Biology, University of Utah, Salt Lake City, UT, USA.
Mol Syst Biol. 2016 Mar 10;12(3):860. doi: 10.15252/msb.20156506.
The signaling events that drive familial breast cancer (FBC) risk remain poorly understood. While the majority of genomic studies have focused on genetic risk variants, known risk variants account for at most 30% of FBC cases. Considering that multiple genes may influence FBC risk, we hypothesized that a pathway-based strategy examining different data types from multiple tissues could elucidate the biological basis for FBC. In this study, we performed integrated analyses of gene expression and exome-sequencing data from peripheral blood mononuclear cells and showed that cell adhesion pathways are significantly and consistently dysregulated in women who develop FBC. The dysregulation of cell adhesion pathways in high-risk women was also identified by pathway-based profiling applied to normal breast tissue data from two independent cohorts. The results of our genomic analyses were validated in normal primary mammary epithelial cells from high-risk and control women, using cell-based functional assays, drug-response assays, fluorescence microscopy, and Western blotting assays. Both genomic and cell-based experiments indicate that cell-cell and cell-extracellular matrix adhesion processes seem to be disrupted in non-malignant cells of women at high risk for FBC and suggest a potential role for these processes in FBC development.
驱动家族性乳腺癌（FBC）风险的信号事件仍知之甚少。虽然大多数基因组研究都集中在遗传风险变异上，但已知的风险变异最多只占FBC病例的30%。考虑到多个基因可能影响FBC风险，我们推测基于通路的策略，通过检查来自多个组织的不同数据类型，可能会阐明FBC的生物学基础。在本研究中，我们对外周血单核细胞的基因表达和外显子测序数据进行了综合分析，结果表明，在患FBC的女性中，细胞黏附通路存在显著且持续的失调。通过对来自两个独立队列的正常乳腺组织数据应用基于通路的分析方法，也确定了高危女性中细胞黏附通路的失调。我们利用基于细胞的功能试验、药物反应试验、荧光显微镜检查和蛋白质印迹试验，在高危和对照女性的正常原代乳腺上皮细胞中验证了基因组分析结果。基因组和基于细胞的实验均表明，在FBC高危女性的非恶性细胞中，细胞间和细胞与细胞外基质的黏附过程似乎受到了破坏，并提示这些过程在FBC发生发展中可能发挥作用。
