Stem Cells, Wnt Signaling, and Breast Cancer
The breast develops from stem cells capable of both self-renewal and differentiation into progenitor cells, which can proliferate many times and progressively differentiate into fully differentiated cells which make up the bulk of the tissue. In mammary ducts, where breast cancers arise, ductal epithelial cells, alveolar epithelial cells, and myoepithelial cells are the principal differentiated cell types.
To effectively prevent breast cancer initiation and to attack individual breast cancers that do form, we have to understand the interplay of specific oncogenic alterations with specific subsets of breast cells, including stem cells, and to identify oncogenic networks that are crucial in the progression to a transformed state.
This knowledge can only be acquired through prospectively introducing selected oncogenic mutations into different subsets of breast cells (stem cells, progenitor cells, and more differentiated ductal and alveolar epithelial cells), investigating the cellular response in each subset, and discovering what additional oncogenic pathways have to be perturbed in order to achieve the eventual malignant phenotype.
All of these need to occur in the context of normal breast epithelium and stroma. It is impossible to directly seek answers to these questions in healthy women. Cultured cells, xenografts, or even current mouse models are inadequate for addressing these issues. Thus, the initial step of breast carcinogenesis remains largely a mystery, even though it could be a key target for early prevention.
We recently adapted the TVA retroviral gene delivery technology to introduce genetic mutations into selected mammary cells in mice at selected times. This method overcomes many of the shortcomings of existing models, and we are using this third generation mouse model to study how specific subsets of breast cells respond to initiating oncogenes and eventually evolve into cancer, whether the stem cells are especially susceptible, and to how oncogenic pathways—especially the Wnt and HER2/Neu signaling pathways—transform breast cells in vivo. Read more about this new technique which cuts time to screen cancer genes and drugs.
Reproductive history is one of the strongest risk factors for breast cancer — women with a full-term pregnancy at an early age have a 50 percent reduction in life-time risk of breast cancer compared with women who experience pregnancy late or not at all. However, the mechanism for this protection is not understood, partly because it has been difficult to use animal models to study which oncogenic events pregnancy protects against, and which cell types are protected. The TVA technology now allows us to approach these questions effectively.