Role of Cell Division Asymmetry in Breast Cancer Stem Cells

Institution: University of California, San Francisco
Investigator(s): Claudia Petritsch, Ph.D. -
Award Cycle: 2006 (Cycle 12) Grant #: 12IB-0140 Award: $149,990
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2006)
Recent data links adult stem cells to cancer and suggests that it is the mammary stem cell population that gives rise to the tumor and not the differentiated, epithelial cell pool. Indeed a small fraction of “cancer stem cells” has been identified in a variety of tumors including mammary tumors. As one piece of evidence confirming the presence of cancer stem cells, as few as 100 of purified cancer stem cells will form tumors in mice, whereas it tens of thousands of non-stem tumor cells are inactive. Adult stem cells are multipotent (i.e., can give rise to many different cell types), reside in distinct areas of the mammary gland, and are important for tissue repair, growth and maintenance. What remains uncertain are the mechanisms that transform normal stem cells into cancer stem cells. Stem cells have the unique potential to divide asymmetrically to generate daughters of distinct fate, one of which remains a stem cell and the other which turns into a cell committed to differentiation. By dividing asymmetrically, stem cells maintain the stem cell pool and simultaneously generate committed cells that reconstitute the organ.

We hypothesize that an initiating step in breast cancer stem cell generation is a defect in the cell division program of normal mammary stem cells. We aim to test whether defects in asymmetric cell division lead to an accumulation of stem cells that become susceptible to genetic changes leading to tumor formation. Clues to this hypothesis have emerged from studies on fruit flies (Drosophila) and on mice lacking regulators of asymmetric cell division in the brain. It is thought that regulatory genes for stem cell functions are strongly conserved across species.

We will test our hypothesis by determining the rate and nature of asymmetric cell division in stem cells from both normal mammary glands and in mammary carcinomas of MMTV-Wnt-1 transgenic mice. Further, we will test whether loss of asymmetric cell divisions leads to pre-malignant and/or malignant lesions in the mammary gland. Finally, we will genetically enforce a blockage of asymmetric cell division in mammary stem cells by creating mice that are deficient in a gene, called Lgl-1, in the mammary gland. Lgl-1 is a known and critical regulator of asymmetric cell division and its loss leads to abrogation of asymmetry in stem cells.

Tumor stem cells are known to be very resistant to chemo-and radiation therapies. They remain viable and start to produce new tumor cells while the stem cell-negative tumor cell population is more easily eradicated. This may explain why some breast cancer patients, despite aggressive standard therapy, suffer from tumor recurrence after many years of apparent disease-free survival. The discovery of the cancer stem cell sheds light on the underlying causative events in tumor formation and resistance to treatment. It is conceivable that by targeting a tiny fraction of tumor cells, the stem cell population, the ability of the tumor to re-populate its cells can be eliminated.

Final Report (2008)
Mammary stem cells replenish the mammary gland through cycles of pregnancy and lactation. Breast cancers contain a small population of stem cells, the breast cancer stem cells. Importantly, breast cancer stem cells are more resistant to existing therapy as other tumor cells, which may explain why some breast cancer patients, despite aggressive therapies, suffer from tumor recurrence and metastases formation. Our study was designed to uncover the very first changes that normal stem cells undergo when they convert into breast cancer in order to learn how to target breast cancer stem cells more specifically and effectively, and to provide tools for early diagnosis of cancerous breast cells in patients or risk groups.

We proposed the central hypothesis that normal mammary stem cells undergo asymmetric cell divisions to generate another stem cell and a differentiating cell. Mammary stem cells defective for asymmetric cell division generate too many breast cancer stem cells. To study this hypothesis, we have successfully developed a cell-based assay to analyze the rate and nature of asymmetric divisions of mouse mammary stem cells, and we have shown that asymmetric cell divisions are present in the mammary stem cell lineage. To provide the first experimental link of disruption of asymmetric cell division and onset of tumorigenesis, we have isolated mammary stem cells from mouse mammary carcinoma and have identified defects in asymmetric cell division. To further strengthen the link of asymmetric cell division defects and generation of breast cancer stem cells, we experimentally disrupted asymmetric cell division by knocking out Lgl-1, an important regulator of asymmetric cell division in the developing mammary gland. Although these studies were not completed, we have proven feasibility for a transplantation model of defective asymmetric stem cell division.

The human homologue of mouse Lgl-1, called Hugl-1, is lost in 76% of breast cancers. Our future aims are to investigate how Lgl-1 prevents the onset of tumorigenesis by preserving normal asymmetric cell divisions.