Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours^1,2,3. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in mouse mammary tissue, we use lineage tracing to map the fate of wild-type and Brca1^−/−;Trp53^−/− cells, and find that both follow a similar pattern of loss and spread within ducts. Clonal analysis reveals that ducts consist of small repetitive units of self-renewing cells that give rise to short-lived descendants. This offers a first layer of protection as any descendants, including oncogenic mutant cells, are constantly lost, thereby limiting the spread of mutations to a single stem cell-descendant unit. Local tissue remodelling during consecutive oestrous cycles leads to the cooperative and stochastic loss and replacement of self-renewing cells. This process provides a second layer of protection, leading to the elimination of most mutant clones while enabling the minority that by chance survive to expand beyond the stem cell-descendant unit. This leads to fields of mutant cells spanning large parts of the epithelial network, predisposing it for transformation. Eventually, clone expansion becomes restrained by the geometry of the ducts, providing a third layer of protection. Together, these mechanisms act to eliminate most cells that acquire somatic mutations at the expense of driving the accelerated expansion of a minority of cells, which can colonize large areas, leading to field cancerization.

致癌突变在健康个体的组织中很丰富，但很少形成肿瘤^1,2,3。然而，潜在的保护机制在很大程度上是未知的。为了解决小鼠乳腺组织中的这些机制，我们使用谱系追踪来绘制野生型和 Brca1 ^{- / -} 的命运;Trp53 ^{- / -} 细胞，并发现两者都遵循相似的丢失模式并在导管内扩散。克隆分析表明，导管由自我更新的细胞的小重复单元组成，这些细胞会产生短命的后代。这提供了第一层保护，因为任何后代（包括致癌突变细胞）都会不断丢失，从而限制突变扩散到单个干细胞后代单位。在连续的发情周期中，局部组织重塑导致自我更新细胞的协作和随机丢失和替换。这个过程提供了第二层保护，导致大多数突变克隆被消除，同时使偶然存活的少数克隆能够扩展到干细胞后代单位之外。这导致突变细胞区域跨越上皮网络的大部分，使其易于转化。最终，克隆扩展受到管道几何形状的限制，从而提供第三层保护。这些机制共同作用，以驱动少数细胞的加速扩增为代价来消除大多数获得体细胞突变的细胞，这些细胞可以在大面积定植，导致野癌化。