In cancer, metastatic disease and recurrence are hypothesized to result from the residual Cancer Stem Cells (CSCs) that evade initial treatment. Therefore, identification of these cells and pathways important in their self-renewal and survival is essential for improvement of current treatments. CSCs are defined as rare cancer cells with stem cell properties, including the capacity to self-renew and the ability to differentiate into multiple cell types. These cells may arise from transformations in early progenitor or stem cells, or differentiated progenitors that regain the ability to self-renew. Putative human mammary cancer stem cells have been identified based on their expression of specific cell surface markers. The human breast cancer CD44⁺/CD24^-/low/lin^-- subpopulation is more tumorigenic compared to other subpopulations by xenograft tumor studies. Also in vitro CD44⁺/CD24^-/low/lin^- cells can form non-adherent spheres, or mammospheres (MS), that also have the potential to self-renew and differentiate. 

We will be investigating treatment targets by examining pathways important in self-renewal and survival of CSCs. Bmi-1 is essential for self-renewal in several different tissues and is highly expressed in different stem cell and cancer cell populations including hematopoietic and neuronal cells. A conserved Bmi-1 driven pathway involved in both normal stem cells and a subset of highly malignant cancers including breast cancer was identified by a clinical transcriptional profiling study. The clinical data along with the self-renewal properties make Bmi-1 an important pathway to investigate in CSCs.

In addition to elucidating pathways that regulate CSC self-renewal, we will also investigate survival of CSCs in response to hyperthermia alone and as a radiosensitizing agent. Historically, there are many studies suggesting that hyperthermia can affect cancer cell survival, and is an effective radiosensitizer. Our initial focus will be on the transplantable p53 null mouse mammary cancer model, and later with human breast tumor samples. Preliminary results using radioresistant cell lines and a tumor initiating subpopulation of p53 null tumor cells in a MS assay indicate the putative CSCs may be thermosensitive. These results suggest that tumorigenic mammary stem/progenitor cells may be sensitive to hyperthermia.

Despite advances in earlier detection, as well as improvements in treatment of breast cancer, 20 percent of women die within 10 years of initial diagnosis due to relapse or metastatic disease. These cases of relapse and metastasis may be due to residual CSCs that are intrinsically resistant to conventional therapies that target highly proliferative cells. Although conventional treatments decrease tumor mass and have been proven effective for some patients, new therapeutic approaches are needed for the subset of women that experience recurrence and metastatic disease after removal of the primary tumor.