Mutant cells colonize healthy tissues over our lifetime, yet it is unclear how these mutant cells spread within a tissue and why the tissue does not transform more readily. As such, mutations alone must be insufficient to make a tumour. Therefore, Ciwinska et al. asked whether natural tissue remodelling might be able to drive mutant cell expansion and, in doing so, identified three protective mechanisms occurring in the healthy mouse mammary gland that constrain the ability of mutant cells to transform and give rise to cancer.

The mammary epithelium consists of long-lived, self-renewing mammary stem cells that give rise to short-lived descendants. As a first level of protection, the authors observed that 80–90% of the Brca1−/−;Trp53−/− mutant cells were lost over time owing to homeostatic tissue turnover, indicating that only the few remaining clones with long-lived stem cell potential can expand throughout the mammary epithelium.