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. 2024 Nov 11;42(11):1936-1954.e9.
doi: 10.1016/j.ccell.2024.09.002. Epub 2024 Oct 3.

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

Pengze Yan  1 , Ernesto Rojas Jimenez  1 , Zheqi Li  1 , Triet Bui  1 , Marco Seehawer  1 , Jun Nishida  1 , Pierre Foidart  1 , Laura E Stevens  1 , Yingtian Xie  2 , Miguel Munoz Gomez  2 , So Yeon Park  3 , Henry W Long  2 , Kornelia Polyak  4
Affiliations

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

Pengze Yan et al. Cancer Cell. .

Abstract

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.

Keywords: aging; breast cancer risk; breast tumorigenesis; mammary tumors; midkine; single-cell profiling.

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Conflict of interest statement

Declaration of interests K.P. serves on the Scientific Advisory Board of Ideaya Biosciences and Scorpion Therapeutics, holds equity options in Scorpion Therapeutics and Ideaya Biosciences, and receives sponsored research funding from Novartis where she also consults. L.E.S. is current employee of Astra-Zeneca. H.W.L. receives research funding from Novartis.

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