We are extending our analysis of cellular subpopulations in the normal mammary epithelium to examine which different cell types are present in tumours arising in genetic models of breast cancer.

We are examining the cell types to determine whether they correspond to cell types in the normal gland and which, if any, have tumour stem cell activity. We are also trying to understand how the relationship between genetic mutations and the cells in which they arise generates different tumour types. In other words, do the same mutations, occurring in two different cell types (for instance luminal estrogen receptor negative breast cells compared to basal breast cells) give rise to the same tumour type or to different types? We have used a lineage analysis approach to identify specific cell populations within the mammary epithelium and then, by combining this knowledge with targeted genetic models, blocked the function of tumour suppressor genes (e.g. Brca1, Brca2, p53 and/or Pten) in these specific cell types. By a comparative analysis of the tumour types that have developed, we have determined that loss of function of different tumour suppressor genes in the same cell type results in very different tumours. This suggests that the genetic changes that cause tumour development are (at least in the models we have examined) dominant over the cell of origin. Such an understanding of the cellular origin of tumours and their relationship to stem cells will be a major advance in our understanding of breast cancer and will enable current and novel therapies to be targeted at the tumour types which will be most responsive to them.