Although aging is one of the strongest risk factors for breast cancer, the mechanisms by which aging promotes tumor initiation and progression are still unclear. A new study in rats might have found the missing link by showing that a growth factor called midkine is upregulated during aging and promotes breast cancer development.

The investigators first performed a comprehensive characterization of the mammary glands from female Fischer 344 rats at ages 3, 6, 12 and 22 months, using single-cell transcriptome and chromatin accessibility sequencing. Their findings revealed several cellular and molecular changes in the mammary gland during aging, including loss of naive T and B cells, expansion of monocyte-derived macrophages and a reduction in collagen production, suggesting a shift to a more cancer-prone environment with age. The team also discovered a luminal progenitor population enriched specifically in old rats, with an expression profile indicative of a precancerous state.

Next, the investigators showed that the expression of midkine — a heparin-binding growth factor overexpressed in various tumors — increased at both the mRNA and protein levels in the rat mammary gland with aging. Midkine treatment of young rats mimicked the transcriptional changes identified in the mammary gland of older rats and promoted nitroso-N-methylurea (NMU)-induced mammary tumorigenesis. To date, the NMU-induced mammary tumor model is the only preclinical immunocompetent model for hormone-dependent estrogen receptor-positive (ER+) mammary tumors. Given that it is the most common subtype, especially in postmenopausal women, the NMU breast cancer model is therefore an ideal platform to study the mechanisms underlying mammary tumor development.

Finally, human data analysis revealed that midkine levels also increase with age in human blood and that elevated midkine levels were associated with an increased risk of breast cancer in young women.

These findings, combining human data and insights from a relevant translational animal model, provide an important biological link between aging and cancer and identify midkine as both a biomarker of aging and breast cancer risk.

Original reference: Yan, P. et. al. Cancer Cell https://doi.org/10.1016/j.ccell.2024.09.002 (2024)