Mammary Stem Cells and Cancer

Previous and current research
My previous research has focused on identifying stem and progenitor cells in both the human and mouse mammary glands. I am interested in these cells because cancer theory suggests that it is these cells that are the initial targets for malignant transformation. The reason for this is that only these cells have the capacity to generate the large numbers of progeny required such that the probability of obtaining subsequent genetic mutations becomes likely. As well, the self-renewal properties of stem cells can be harnessed by cancer stem cells to propagate the malignancy.

It is now apparent that cells that meet the functional definition of a mammary gland stem cell (i.e., can generate the entire mammary epithelium with all its lineages and can self-renew) can be detected within the mouse mammary epithelium. These cells reside within the basal compartment of the mammary gland, and can be isolated by flow cytometry on the basis of their CD24⁺CD49f⁺⁺ phenotype and can be detected by in vivo functional assays. Cells that display similar properties can also be identified in the human mammary gland.

Another focus of the laboratory is the characterization of the different types of cells other than stem cells that are present within the mammary epithelium and determining the relationship of these cells with one another within the mammary epithelial cell hierarchy. An understanding of this hierarchy is essential for understanding the considerable heterogeneity of breast cancer. For example, it is not known if this heterogeneity is due to tumours originating in different types of cells and the gene expression pattern of a tumour just reflecting the cell of origin, or if all tumours originate in stem cells and the type of tumour generated is just a reflection of the molecular pathways perturbed during the evolution of the tumour, or if it is a combination of the two processes. Understanding the origins of breast tumours and the unique properties of breast cancer stem cells will be essential in the development of rational therapeutic strategies to cure this disease.

Future Projects

• To determine the gene expression profiles of mammary stem and progenitor cells and to characterize the molecular mechanisms that regulate their behavior.
• To study the influence of common breast cancer mutations on mammary stem and progenitor function.
• To characterize the mechanisms regulating symmetric cell division in mammary epithelial stem cells.
• To characterize the cell of origin and the evolution of cancer stem cells in different molecular subtypes of human breast tumours.