Field cancerization in mammary tissue is driven by protection mechanisms that clear mutations. null

Oncogenic mutations are abundantly present in tissues of healthy individuals, but rarely cause tumor formation. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in murine breast tissues, we studied the fate of epithelial cells that acquire oncogenic (Brca1-/-;Trp53-/-) mutations with those bearing neutral mutations. We find that oncogenic and neutral mutant clones follow similar dynamics and both spread within the ducts leading to cohesive clonal fields spanning large parts of the ductal epithelial network thereby predisposing it prone for transformation. Clonal analysis reveals that the ductal network is maintained by a population of self-renewing cells (termed mammary stem cells or enduring progenitors) that stand at the apex of a short hierarchy comprising of cells with strictly limited self-renewal potential. This hierarchy confers a first layer of protection as all the cells, including the oncogenic mutant cells, with limited self-renewal potential have a high probability of being lost. Local tissue remodeling during the estrous cycle leads to stochastic and local collective loss and replacement of self-renewing cells. This process provides a second mechanism of protection, leading to the elimination of the majority of mutant clones, while massively accelerating the expansion of the minority of clones that, by chance, survive. Eventually, this “inflationary” process of geometric clone expansion becomes restrained by the one-dimensional geometry of the ducts, providing a third mechanism to protect the epithelium against uncontrolled colonization by mutant clones. Together, these findings reveal layers of protection that serve to eliminate the majority of 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.