The hypothesis that tumour phenotype reflects the cellular origin of that tumour has recently gained momentum as an explanation to address the heterogeneity observed among breast and other epithelial tumours. In this light it has become unclear what role, if any, the underlying mutational landscape of a tumour plays in determining tumour phenotype.
To address this, we purified phenotypically distinct subpopulations of freshly isolated non-cultured human mammary epithelial cells. Each subpopulation was transformed using two combinations of Lentiviral-induced genetic events and implanted in vivo. The resulting tumour phenotypes were assessed histologically and by using global RNA/DNA profiling.
Our data clearly show that transformation of stem, progenitor and differentiated cells from the same donors give rise to phenotypically indistinguishable tumours. These data demonstrate that under these conditions, cell-of-origin plays little if any role in dictating tumour phenotype. Further, we show that transformation by means of subtly different genetic events gives rise to tumours of a distinct phenotype that is once again independent of cellular context. We are now focusing efforts on understanding just how subtle changes in genetic drivers leads to divergent tumour phenotypes.