Cellular plasticity and metastasis in breast cancer: a pre- and post-malignant problem

As a field we have made tremendous strides in treating breast cancer, with a decline in the past 30 years of overall breast cancer mortality. However, this progress is met with little affect once the disease spreads beyond the primary site. With a 5-year survival rate of 22%, 10-year of 13%, for those patients with metastatic breast cancer (mBC), our ability to effectively treat wide spread disease is minimal. A major contributing factor to this ineffectiveness is the complex make-up, or heterogeneity, of the primary site. Within a primary tumor, secreted factors, malignant and pre-malignant epithelial cells, immune cells, stromal fibroblasts and many others all reside alongside each other creating a dynamic environment contributing to metastasis. Furthermore, heterogeneity contributes to our lack of understanding regarding the cells' remarkable ability to undergo epithelial/non-cancer stem cell (CSC) to mesenchymal/CSC (E-M/CSC) plasticity. The enhanced invasion & motility, tumor-initiating potential, and acquired therapeutic resistance which accompanies E-M/CSC plasticity implicates a significant role in metastasis. While most work trying to understand E-M/CSC plasticity has been done on malignant cells, recent evidence is emerging concerning the ability for pre-malignant cells to undergo E-M/CSC plasticity and contribute to the metastatic process. Here we will discuss the importance of E-M/CSC plasticity within malignant and pre-malignant populations of the tumor. Moreover, we will discuss how one may potentially target these populations, ultimately disrupting the metastatic cascade and increasing patient survival for those with mBC.