乳腺癌
上皮
癌症研究
基质
蛋白激酶B
间质细胞
乳腺照相密度
癌基因
内科学
生物
化学
医学
病理
内分泌学
信号转导
癌症
细胞生物学
免疫组织化学
乳腺摄影术
细胞周期
作者
Jason J. Northey,Alexander Barrett,Irene Acerbi,Mary-Kate Hayward,Stephanie Talamantes,Ivory Dean,Janna K. Mouw,Suzanne M. Ponik,Johnathon N. Lakins,Po-Jui Huang,Junmin Wu,Quanming Shi,Susan L. Samson,Patricia J. Keely,Rita A. Mukhtar,Jan Liphardt,John Shepherd,E. Shelley Hwang,Yunn-Yi Chen,Kirk C. Hansen,Laurie E. Littlepage,Valerie M. Weaver
摘要
Women with dense breasts have an increased lifetime risk of malignancy that has been attributed to a higher epithelial density. Quantitative proteomics, collagen analysis, and mechanical measurements in normal tissue revealed that stroma in the high-density breast contains more oriented, fibrillar collagen that is stiffer and correlates with higher epithelial cell density. microRNA (miR) profiling of breast tissue identified miR-203 as a matrix stiffness–repressed transcript that is downregulated by collagen density and reduced in the breast epithelium of women with high mammographic density. Culture studies demonstrated that ZNF217 mediates a matrix stiffness– and collagen density–induced increase in Akt activity and mammary epithelial cell proliferation. Manipulation of the epithelium in a mouse model of mammographic density supported a causal relationship between stromal stiffness, reduced miR-203, higher levels of the murine homolog Zfp217, and increased Akt activity and mammary epithelial proliferation. ZNF217 was also increased in the normal breast epithelium of women with high mammographic density, correlated positively with epithelial proliferation and density, and inversely with miR-203. The findings identify ZNF217 as a potential target toward which preexisting therapies, such as the Akt inhibitor triciribine, could be used as a chemopreventive agent to reduce cancer risk in women with high mammographic density.
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