Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer risk

• Published in: Cell stem cell 2024-01, Vol.31 (1), p.106-126.e13
• Main Authors: Northey, Jason J., Hayward, Mary-Kate, Yui, Yoshihiro, Stashko, Connor, Kai, FuiBoon, Mouw, Janna K., Thakar, Dhruv, Lakins, Jonathon N., Ironside, Alastair J., Samson, Susan, Mukhtar, Rita A., Hwang, E. Shelley, Weaver, Valerie M.
• Format: Article
• Language: English
• Subjects: Animals; breast cancer risk; Breast Neoplasms; Epithelial Cells; extracellular matrix stiffness; Extracellular Signal-Regulated MAP Kinases; Female; Hormones; Humans; integrin signaling; mammary progenitor cells; mammographic density; mechanobiology; Mice; RANK; RANKL; Signal Transduction
• ISSN: 1934-5909; 1875-9777; 1875-9777
• 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. [Display omitted] •Integrin mechanosignaling expands mammary epithelial stem-progenitors•Mechanosensitive ERK-PR promotes RANK signaling to expand stem-progenitor cells•Mechanosignaling and RANK-driven stem-progenitor expansion enhance tumor initiation•Patients with dense breasts exhibit integrin/ERK/PR/RANKL-induced stemness Weaver and colleagues uncover a role for integrin mechanosignaling in promoting mammary epithelial stem-progenitor cell frequency and fostering tumor initiation and implicate mechanosensitive ERK-PR-induced RANK signaling in driving this process. Inhibiting these pathways could reduce cancer risk in women with high mammographic density.