美国加州大学Valerie M. Weaver团队近期取得重要工作进展，他们研究发现，机械敏感激素信号能促进乳腺祖细胞扩张和乳腺癌风险。相关研究成果2024年1月4日在线发表于《细胞—干细胞》杂志上。

据介绍，组织干祖细胞频率与肿瘤风险和进展有关，但将这些关联联系起来的组织特异性因素仍不明确。

研究人员观察到，乳房X光检查密度高的女性，其患癌症的风险增加，这种坚硬的乳房组织与大量的干细胞相关。使用整合素机械信号和胶原密度升高的基因工程小鼠模型、同源操作和球体模型，研究人员确定刚性基质和高机械信号增加了乳腺上皮干祖细胞的频率，并增强了体内肿瘤的发生风险。增强的组织力学通过增强细胞外信号相关激酶（ERK）活性来促进孕酮受体依赖性RANK信号传导，从而扩大干性。研究人员一致地检测到，在高乳房X光检查密度女性的僵硬乳房组织中，磷酸化ERK和孕酮受体升高，RANK信号水平升高。

总之，这些发现将纤维化和机械信号传导与干-生殖细胞频率和乳腺癌症风险联系起来，并在这种表型中导致表皮生长因子受体依赖性激素信号传导。

附：英文原文

Title: Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer risk

Author: 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

Issue&Volume: 2024/01/04

Abstract: Tissue stem-progenitor cell frequency has been implicated in tumor risk and progression,but tissue-specific factors linking these associations remain ill-defined. We observedthat stiff breast tissue from women with high mammographic density, who exhibit increasedlifetime risk for breast cancer, associates with abundant stem-progenitor epithelialcells. Using genetically engineered mouse models of elevated integrin mechanosignalingand collagen density, syngeneic manipulations, and spheroid models, we determinedthat a stiff matrix and high mechanosignaling increase mammary epithelial stem-progenitorcell frequency and enhance tumor initiation in vivo. Augmented tissue mechanics expand stemness by potentiating extracellular signal-relatedkinase (ERK) activity to foster progesterone receptor-dependent RANK signaling. Consistently,we detected elevated phosphorylated ERK and progesterone receptors and increased levelsof RANK signaling in stiff breast tissue from women with high mammographic density.The findings link fibrosis and mechanosignaling to stem-progenitor cell frequencyand breast cancer risk and causally implicate epidermal growth factor receptor-ERK-dependenthormone signaling in this phenotype.

DOI: 10.1016/j.stem.2023.12.002

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00432-0