Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, CA 94143, USA.
Research Institute, Nozaki Tokushukai Hospital, Tanigawa 2-10-50, Daito, Osaka 574-0074, Japan.
Cell Stem Cell. 2024 Jan 4;31(1):106-126.e13. doi: 10.1016/j.stem.2023.12.002.
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.
组织干细胞-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未明确界定。我们观察到，来自乳腺 X 光密度高的女性的坚硬乳房组织与丰富的干细胞-祖细胞上皮细胞有关，这些女性表现出一生中乳腺癌风险增加。使用整合素机械信号转导和胶原密度升高的基因工程小鼠模型、同种异体操作和球体模型，我们确定坚硬的基质和高机械信号转导增加了乳腺上皮干细胞-祖细胞的频率，并增强了体内肿瘤的起始。增强的组织力学通过增强细胞外信号相关激酶 (ERK) 活性来扩大干性，以促进孕激素受体依赖性 RANK 信号。一致地，我们在乳腺 X 光密度高的女性的坚硬乳房组织中检测到磷酸化 ERK 和孕激素受体的升高以及 RANK 信号的增加。这些发现将纤维化和机械信号转导与干细胞-祖细胞频率和乳腺癌风险联系起来，并因果关系地将表皮生长因子受体-ERK 依赖性激素信号转导与此表型联系起来。
