I am interested in cancer stem cells or tumor initiating cells (TIC) in breast cancer.  Evidence has shown that these cells may have an intrinsic resistance to radiation and chemotherapeutics compared to the bulk of the tumor.  These cells also may be responsible for metastatic dissemination and tumor dormancy and recurrence.  Therefore, it is important to understand the biology of TIC in order to develop targeted therapies to eradicate these cells.
Genomic profiling of human breast tumors has classified them into several distinct and clinically relevant groups (basal-like, luminal A, luminal B, HER2+/ER-, and normal-like).  During my graduate studies, we identified a new and rare molecular subtype of human breast cancer which we refer to as the Claudin-low group.  Like basal-like tumors, these tumors are generally triple negative (ER-, PR-, HER2-), however they uniquely express low levels of tight and adherens junction genes including Claudin 3 and E-cadherin.  Claudin-low tumors also often highly express markers associated with epithelial to mesenchymal transition (EMT).  It has since been shown that a signature derived from human TICs is both enriched post-treatment and also in the Claudin-low subtype.  Through comparative genomics, we have discovered that there are mouse mammary tumors that have similar gene expression characteristics as Claudin-low human tumors.   Tumors in this group were rare tumors which came from a number of distinct mouse models including the p53 null transplant model.  We have now collected more tumors from the p53 null model in order to identify Claudin-low/spindloid tumors that we can transplant and expand in vivo with the goal of using this tumor bank for mechanistic and preclinical studies.  The p53 null tumor model offers several advantages over other models including the ability to transplant the tumors into syngeneic mice.   We are currently characterizing the p53 spindloid tumors as compared to the more common adenocarcinomas arising in the same model.
Our lab has analyzed a series of p53 null transplant adenocarcinomas (non-spindloid) for their expression of mammary stem cell related surface markers.  The CD29+/CD24+ population marked the TIC in all the tumors analyzed by limiting dilution transplantation.  Gene expression profiling identified several genes/pathways upregulated including the polycomb group genes Bmi-1 and Ezh2.  I am currently investigating how these genes regulate cancer stem cell self-renewal.  Overall, my goal is to understand the biology of cancer stem cells which will enable the development of targeted therapeutic strategies to eliminate them.