The canonical NF-B pathway is required for formation of luminal mammary neoplasias and is activated in the mammary progenitor population

The role of the canonical NF-B pathway in mammary tumorigenesis was investigated using a transgenic (TG) mouse expressing a dominant-negative inhibitor of B (IBα^{SR(S32A/S36A)}) in the mammary gland under the control of the mouse mammary tumor virus promoter (MMTV). TG and control mice were subjected to a chemical carcinogenesis protocol. Hyperkeratinized squamous metaplasias (cytokeratin6/p63) sometimes with a basaloid island component, were found in both TG and control mice whereas luminal (cytokeratin-19/MUC1) ErbB2 papillary and adenomatous lesions developed almost exclusively in control mice. p65/RelA- and NF-B DNA-binding activity were detected in mammary luminal lesions, but rarely in squamous metaplasias. Analysis of NF-B family proteins and target genes using microarray data from a cohort of human mammary tumors revealed the expression of a canonical NF-B pathway, but not non-canonical pathway proteins in HER2 luminal cancers. HER2 tumors also showed differential regulation of specific NF-B target genes relative to basal and ER luminal cancers. Isolation of mammary cell populations enriched for stem and progenitor cell characteristics from an NF-B-EGFP reporter mouse by fluorescence-activated cell sorting demonstrated that luminal progenitors contain activated NF-B whereas the mammary stem cell-enriched population, does not. Together these data suggest that the canonical NF-B pathway is active in normal luminal progenitor cells before transformation and is required for the formation of mammary luminal-type epithelial neoplasias.