Abstract
Chemotherapeutic strategies that target basal-like breast tumors are difficult to design without understanding their cellular and molecular basis. Here, we induce tumors in mice by carcinogen administration, creating a phenocopy of tumors with the diagnostic and functional aspects of human triple negative disease (including EGFR expression/lack of erbB, estrogen-independent growth and co-clustering of the transcriptome with other basaloid models). These tumor strains are a complement to established mouse models that are based on mutations in Brca1 and/or p53. Tumors comprise two distinct cell subpopulations, basal and luminal epithelial cells. These cell fractions were purified by flow cytometry, and only basal cell fractions found to have tumor initiating activity (cancer stem cells). The phenotype of serially regenerated tumors was stable, and irrespective of tumor precursor cell. Tumors were passaged entirely in vivo and serial generations tested for their phenotypic stability. The relative chemo-sensitivity of basal and luminal cells were evaluated. Upon treatment with anthracycline, tumors were effectively de-bulked, but recurred; this correlated with maintenance of a high rate of basal cell division throughout the treatment period. Thus, these tumors grow as robust cell mixtures of basal bipotential tumor initiating cells alongside a luminal majority, and the cellular response to drug administration is dominated by the distinct biology of the two cell types. Given the ability to separate basal and luminal cells, and the discovery potential of this approach, we propose that this mouse model could be a convenient one for preclinical studies.