Keratin 6a marks mammary bipotential progenitor cells that can give rise to a unique tumor model resembling human normal-like breast cancer

Abstract

Progenitor cells are thought to be an important cell of origin of human malignancies. However, there has not been any single gene that can define mammary bipotential progenitor cells, and as such it has not been possible to use genetic methods to introduce oncogenic alterations into these cells in vivo to study tumorigenesis from them. Keratin 6a is expressed in a subset of mammary luminal epithelial cells and body cells of terminal end buds. By generating transgenic mice using the Keratin 6a (K6a) gene promoter to express tva, which encodes the receptor for avian leukosis virus subgroup A (ALV/A), we provide direct evidence that K6a+ cells are bipotential progenitor cells. These K6a+ cells were readily induced to form mammary tumors by intraductal injection of RCAS (an ALV/A-derived vector) carrying the gene encoding the polyoma middle T antigen. Tumors in this K6a-tva line were unique in that they resemble the normal breast-like subtype of human breast cancer, providing a model for preclinical testing of targeted therapy for patients with normal-like breast cancers. These observations also provide direct in vivo evidence for the hypothesis that the cell of origin affects mammary tumor phenotypes.