Prolactin modulates TNBC aggressive phenotype limiting tumorigenesis

: Triple negative breast cancer (TNBC) accounts for ~20% of all breast cancer cases. The management of TNBC represents a challenge due to its aggressive phenotype, heterogeneity and lack of targeted therapy. Loss of cell differentiation and enrichment with breast cancer stem-like cells (BCSC) are features of TNBC contributing to its aggressive nature. Here, we found that PRL treatment of TNBC cells to significantly depletes the highly tumorigenic BCSC subpopulations CD44+/CD24- and ALDH+ and differentiate them to the least tumorigenic CD44-/CD24- and ALDH- phenotype with limited tumorsphere formation and self-renewal capacities. Importantly, we found PRL to induce a heterochromatin phenotype marked by histone H3 lysine 9 trimethylation (H3K9me3) and accompanied by ultrastructural cellular architecture associated with differentiation and senescence rendering the cells refractory to growth signals. Crucially, we found PRL to mediate these effects in vivo in a preclinical animal xenograft of TNBC controlling tumor growth. These results reveal that the lactogenic hormone PRL may exert its anti-tumorigenic effects in TNBC through cellular reprogramming indicative of differentiation resulting in depletion of BCSCs and restricting tumorigenesis.