Jason J. Northey, Mary-Kate Hayward, Yoshihiro Yui, Connor Stashko, FuiBoon Kai, Janna K. Mouw, Dhruv Thakar, Jonathon N. Lakins, Alastair J. Ironside, Susan Samson, Rita A. Mukhtar, E. Shelley Hwang, Valerie M. Weaver
{"title":"机敏激素信号促进乳腺祖细胞扩增和乳腺癌风险","authors":"Jason J. Northey, Mary-Kate Hayward, Yoshihiro Yui, Connor Stashko, FuiBoon Kai, Janna K. Mouw, Dhruv Thakar, Jonathon N. Lakins, Alastair J. Ironside, Susan Samson, Rita A. Mukhtar, E. Shelley Hwang, Valerie M. Weaver","doi":"10.1016/j.stem.2023.12.002","DOIUrl":null,"url":null,"abstract":"<p><span>Tissue stem-progenitor cell frequency has been implicated in tumor risk and progression, but tissue-specific factors linking these associations remain ill-defined. We observed that stiff breast tissue from women with high mammographic density, who exhibit increased lifetime risk for breast cancer, associates with abundant stem-progenitor epithelial cells. Using genetically engineered mouse<span><span> models of elevated integrin<span> mechanosignaling and collagen density, </span></span>syngeneic<span> manipulations, and spheroid<span> models, we determined that a stiff matrix and high mechanosignaling increase mammary epithelial stem-progenitor cell frequency and enhance tumor initiation </span></span></span></span><em>in vivo</em>. Augmented tissue mechanics expand stemness by potentiating extracellular signal-related kinase (ERK) activity to foster progesterone receptor-dependent RANK signaling. Consistently, we detected elevated phosphorylated ERK and progesterone receptors and increased levels of RANK signaling in stiff breast tissue from women with high mammographic density. The findings link fibrosis and mechanosignaling to stem-progenitor cell frequency and breast cancer risk and causally implicate epidermal growth factor receptor-ERK-dependent hormone signaling in this phenotype.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":null,"pages":null},"PeriodicalIF":19.8000,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer risk\",\"authors\":\"Jason J. Northey, Mary-Kate Hayward, Yoshihiro Yui, Connor Stashko, FuiBoon Kai, Janna K. Mouw, Dhruv Thakar, Jonathon N. Lakins, Alastair J. Ironside, Susan Samson, Rita A. Mukhtar, E. Shelley Hwang, Valerie M. Weaver\",\"doi\":\"10.1016/j.stem.2023.12.002\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><span>Tissue stem-progenitor cell frequency has been implicated in tumor risk and progression, but tissue-specific factors linking these associations remain ill-defined. We observed that stiff breast tissue from women with high mammographic density, who exhibit increased lifetime risk for breast cancer, associates with abundant stem-progenitor epithelial cells. Using genetically engineered mouse<span><span> models of elevated integrin<span> mechanosignaling and collagen density, </span></span>syngeneic<span> manipulations, and spheroid<span> models, we determined that a stiff matrix and high mechanosignaling increase mammary epithelial stem-progenitor cell frequency and enhance tumor initiation </span></span></span></span><em>in vivo</em>. Augmented tissue mechanics expand stemness by potentiating extracellular signal-related kinase (ERK) activity to foster progesterone receptor-dependent RANK signaling. Consistently, we detected elevated phosphorylated ERK and progesterone receptors and increased levels of RANK signaling in stiff breast tissue from women with high mammographic density. The findings link fibrosis and mechanosignaling to stem-progenitor cell frequency and breast cancer risk and causally implicate epidermal growth factor receptor-ERK-dependent hormone signaling in this phenotype.</p>\",\"PeriodicalId\":9665,\"journal\":{\"name\":\"Cell stem cell\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":19.8000,\"publicationDate\":\"2024-01-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell stem cell\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.stem.2023.12.002\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL & TISSUE ENGINEERING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell stem cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.stem.2023.12.002","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}
Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer risk
Tissue stem-progenitor cell frequency has been implicated in tumor risk and progression, but tissue-specific factors linking these associations remain ill-defined. We observed that stiff breast tissue from women with high mammographic density, who exhibit increased lifetime risk for breast cancer, associates with abundant stem-progenitor epithelial cells. Using genetically engineered mouse models of elevated integrin mechanosignaling and collagen density, syngeneic manipulations, and spheroid models, we determined that a stiff matrix and high mechanosignaling increase mammary epithelial stem-progenitor cell frequency and enhance tumor initiation in vivo. Augmented tissue mechanics expand stemness by potentiating extracellular signal-related kinase (ERK) activity to foster progesterone receptor-dependent RANK signaling. Consistently, we detected elevated phosphorylated ERK and progesterone receptors and increased levels of RANK signaling in stiff breast tissue from women with high mammographic density. The findings link fibrosis and mechanosignaling to stem-progenitor cell frequency and breast cancer risk and causally implicate epidermal growth factor receptor-ERK-dependent hormone signaling in this phenotype.
期刊介绍:
Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.