Progress towards an understanding of radiation-induced mammary cancer using a murine model
Date
2009
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Abstract
Theoretically, any exposure to ionizing radiation (IR) results in an increased risk of developing breast cancer. We have used a mouse model of radiation-induced breast cancer to study the effects of genetic background and molecular mechanisms of carcinogenesis. The BALB/c mouse strain is susceptible to radiation-induced mammary cancer while other laboratory strains are not. In this dissertation telomere-specific FISH was used to show that mammary epithelial cells derived from BALB/cByJ mice develop significantly more telomere-DSB fusions after IR exposure compared to those derived from C57BL/6J mice. The kinetics of telomere instability follow the same kinetics as the strain-specific genomic instability observed in earlier studies. An experimental system involving transplantation of cells from the breast of one mouse and regenerated in another mouse has been used extensively to demonstrate the genetic susceptibility of the BALB/c mouse to radiation-induced mammary cancer. The numbers of cells necessary for successful transplantation suggests that the cell capable of regenerating a mammary gland is a rare cell, perhaps a pluripotent stem cell. In this dissertation detailed protocols were created for isolation and tissue culture of murine mammary stem cells as mammospheres grown at high density, clonal density, and grown in basement membrane extract. A great deal of size variation was found in each culture of mammospheres. To test the hypothesis that only large mammospheres contained true stem cells the self-renewal capacity of specific sizes of mammospheres was tested using serial passaging. The data suggest that cells derived from larger mammospheres are capable of more passages than small mammospheres. Additionally, mammospheres were dissociated and tested for the presence of multiple cell lineages, as expected for pluripotent cells. Finally, we developed an assay to assess the radiation response of mammospheres derived from five strains of inbred mouse related to the BALB/c model of radiation-induced mammary cancer. These data show that mammary stem cells are more resistant to the killing effects of IR than fibroblasts derived from the same strains of mice. The data also show varying radiation sensitivities between genetically distinct mouse strains.
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Subject
breast cancer
ionizing radiation
mammary stem cells
radiation-induced cancer
cellular biology
radiation