Development of breast cancer stem cells
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: 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.