Human breast cancer is a heterogeneous disease; composed of moderate well-differentiated subtypes as well as aggressive undifferentiated subtypes each with distinct clinical behavior, and unique marker expression. Tumors of the “basal-like” subtype exhibit poor differentiation and aggressive clinical behavior, yet it is currently unclear what factors drive this differentiation state and no targeted therapy currently exists to treat these malignancies. The central aim of our study is to uncover regulatory genes that determine the subtype identity of breast cancer cells, and thereby their aggressive traits.
In our previous study we studied the function of the master-regulator EZH2 in tumors of the basal-like subtype, and established it as a regulator of the aggressive identity of these tumors and a driver of progenitor-like markers and traits. We have also identified the existence of a subpopulation of cells with progenitor-like features, found in basal-like cell lines and patient tumor samples, and marked by co-expression of markers of both lineages of the normal breast – thus termed “bi-lineage” cells. We found that this population is maintained by EZH2 both in vitro and in vivo, and its reduction might be responsible for the observed change in tumor identity. We are currently working to further characterize the presence and function of the bi-lineage cells in tumor initiation and progression and are working to dissect the regulatory networks that govern the basal-like differentiation state. To do so we are conducting a broad-scale shRNA screen, based on the tools we have developed thus far, to detect additional functional regulators of the basal-like state.
