Rank signaling drives basal cell-lineage infidelity leading to mammary tumorigenesis.

Rank signaling regulates mammary gland development and epithelial differentiation. While Rank is expressed in both basal and luminal cells, its basal-specific role is unclear. Here, using inducible basal-specific Rank expression and lineage tracing, we show that Rank signaling regulates basal cell identity in postnatal mammary glands. Increased basal Rank activity disrupts basal and luminal identities, causing aberrant luminal-like differentiation, lactation defects, and premalignant lesions composed of hybrid basal-derived cells that progress to basal and luminal adenocarcinomas. Conversely, Rank loss reduces tumor formation and also impairs cell identity. Mechanistically, proteomic, transcriptomic, and chromatin analyses reveal that Rank activation drives epigenetic remodeling, leading to basal identity loss and tumor initiation. A basal Rank gene signature correlates with ductal carcinoma in situ recurrence, as well as poor outcomes in luminal breast cancers. Thus, basal Rank-driven lineage infidelity promotes pre-invasive lesions and transition to invasive breast cancer in females.