Despite many recent advances, breast cancer remains a poorly understood disease with a bad outcome for many women. It is becoming clear that progress in treating breast cancer effectively requires a much better understanding of the cells that maintain the tumor populations and exactly how they are abnormal in a given patient. In this project, we will investigate the emerging concept that a breast tumor contains a mixture of different cell types, only a small fraction of which, the "cancer stem cells," are responsible for actually keeping the tumor going. If this hypothesis is correct, studies of the "bulk" tumor may not detect the critical changes in the rare cancer stem cells and may thus "miss the boat" in terms of yielding information that can lead to sustained cures.

Many normal adult tissues have now been found to contain a rare population of stem cells. These cells are defined by their ability to regenerate all of the functional elements of the tissue. The growth and death of normal stem cells are strictly controlled. Perturbation of these control mechanisms can cause a significant overproduction of daughter cells and lead to the formation of a tumor.

This concept of cancers arising in mutated stem cells is well established in leukemia, but is still at a relatively early stage of scientific investigation in breast cancer research. If it proves valid for breast cancer, the therapeutic implications are profound. Treatments that appear to work well initially might not be curative because of their failure to kill the tumor stem cells, thus leaving the regenerative capacity of the cancer intact in spite of an initial marked decrease in the tumor burden. Strategies will then be needed to identify the cancer stem cells and ensure that they are effectively targeted. This, in turn, will require a much better understanding of how their unique biology, regulation, and drug sensitivity are determined, some of which may be borrowed from normal mammary stem cells.

A major hurdle to progress in this important area of research has been a lack of methods to measure, isolate, and characterize human breast stem cells. Recent studies, including work from our laboratory, have shown that such measurements can be performed on mice. Currently, however, methods that allow their human counterparts to be reproducibly identified and studied directly do not exist, although a number of promising leads have been obtained. For example, it has been found that pieces of human breast tissue can be grown after their transplantation into special strains of mice that have no immune system. In addition, recent advances in characterizing primitive human breast cells that can grow in tissue culture have also been made.

In this project, I plan to build on these recent advances to develop a strategy for identifying human mammary stem cells. I will isolate these cells from human tissue samples to obtain them as highly purified populations with the eventual goal of comparing the stem cells in normal breast with breast cancer stem cells. The results will make it possible to begin to understand how normal human breast tissue develops and the role of breast stem cells in the initiation and progression of human breast cancer. They will also set the stage for developing new approaches to assigning breast cancer patients to different prognostic categories and for the testing of new treatments that may target pathways required by human breast cancer stem cells.