Remaining true to one's identity

Abstract

The ability to remain true to cellular identity and function is lost during aging and carcinogenesis when DNA damage triggers inflammation that progressively erodes homeostatic cues. Shalabi et al. show that these losses are accelerated in patients with germline cancer mutations in DNA repair genes and are independent of chronological age.

Fig. 1 |. Germline mutations in BRCA1, BRCA2 and PALB2 compromise DNA damage repair, promote inflammation and accelerate loss of lineage fidelity, thereby contributing to carcinogenesis.

a, Women with average risk of developing breast cancer accumulate DNA damage as a result of exposure to environmental factors. The resulting tissue damage triggers inflammation (amount and duration indicated by purple shapes), which progressively erodes the homeostatic cues that maintain issue identity and function. One manifestation is a loss of luminal epithelial lineage fidelity, as shown by the inappropriate expression of myoepithelial cell markers. Loss of lineage fidelity during aging is correlated with increased cancer incidence. b, Women with germline mutations in BRCA1, BRCA2, or PALB2, who are at high risk of developing breast cancer, begin to accumulate DNA damage much earlier in life. This accelerates the development of an inflammatory state, tissue degradation, loss of luminal epithelial lineage fidelity and, ultimately, carcinogenesis. Inflammatory signaling is concordant with increased risk for cancer and is discordant with chronological aging.