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 . 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.

中文翻译：

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机械敏感激素信号传导促进乳腺祖细胞扩张和乳腺癌风险

组织干祖细胞频率与肿瘤风险和进展有关，但连接这些关联的组织特异性因素仍然不明确。我们观察到，乳房X光密度高的女性的坚硬乳腺组织与丰富的干祖上皮细胞相关，这些女性一生中患乳腺癌的风险增加。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、同基因操作和球体模型，我们确定刚性基质和高机械信号会增加乳腺上皮干祖细胞频率并增强肿瘤发生。增强的组织力学通过增强细胞外信号相关激酶 (ERK) 活性来促进黄体酮受体依赖性 RANK 信号传导，从而扩大干性。一致地，我们在乳房 X 光密度较高的女性的僵硬乳腺组织中检测到磷酸化 ERK 和孕激素受体升高，以及 RANK 信号水平升高。研究结果将纤维化和机械信号传导与干祖细胞频率和乳腺癌风险联系起来，并暗示该表型中表皮生长因子受体 ERK 依赖性激素信号传导。