Midkine as a driver of age-related changes and increase in mammary tumorigenesis.

Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and T cells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis. [Display omitted] • Cellular and molecular changes in the mammary gland with age • Midkine is a key driver of aging-related changes and mammary tumorigenesis • High midkine levels are associated with higher risk of breast cancer in younger women Yan et al. reveal age-related changes in the rat mammary gland, identifying a unique aging-associated luminal progenitor population. Midkine treatment mimics the effects of aging and promotes mammary tumorigenesis. Elevated midkine levels are associated with increased breast cancer risk in younger women highlighting its role in age-related tumor initiation. [ABSTRACT FROM AUTHOR]