Nf1deficiency accelerates mammary development and promotes luminal-basal plasticity

Abstract

SUMMARYThe tumor suppressorNF1is a critical driver of sporadic breast cancer and NF-related breast cancers. We utilized distinctNf1-deficient immunocompetent rat models to investigateNf1function in mammary development and homeostasis. Here we demonstrate thatNf1deficiency dramatically accelerates mammary morphogenesis, alters TEB cell organization, and proliferation. Notably, we observed a shift in luminal-basal epithelial lineage commitment withinNf1-deficient lines with early tumor onset. In addition, we detected subpopulations of hybrid EMT cells (Ecad+/CK14+) within the invasive edge and stroma ofNf1-deficient tumors.Nf1deficiency restricted luminal progenitor potential and resulted in gene expression changes associated with decreased cell adhesion and increased EMT signatures. Together our findings support a model in whichNf1loss of function results in lineage plasticity throughout mammary morphogenesis and promotes EMT-mediated invasion. This study reveals a previously unknown role for the tumor suppressor neurofibromin in mammary homeostasis and phenotypic plasticity during breast cancer progression.