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Open Access Thesis
Master of Science (M.S.)
Year Degree Awarded
Month Degree Awarded
Breast cancer is the leading cause of women’s cancer death in the United States. Estrogen exposure and reproductive history are the greatest influencing factors towards developing breast cancer. The following experiments compare the impact of parity on genomic surveillance as evaluated by radiation sensitivity to treatment with estrogen (E2) and estrogen receptor agonists. Mice are treated with agonists for 14 days and harvested after 5 weeks of involution. Apoptotic response to radiation indicated background estrogen, confounding the results, and failure to elicit appropriate response from E2 treatment. Upon further analysis, the cellulose matrix vehicle was identified as providing biologically active estrogen. To further test the effect of treatment with estrogen receptor specific agonists, a new vehicle for hormone delivery was required.
We tested tocopherol stripped corn oil as an oral vehicle to deliver estrogen agonists; estrogenic background was no longer detected in control-treated animals. E2 treatment increased apoptosis, development, and gene expression in the mammary gland of mice treated for 4 days. Treatment with estrogen receptor agonists PPT and DPN was unable to alter apoptosis but did impact uterine wet weights and gene expression within the mammary glands. These results indicated that treatment, while not completely effective, may still be biologically absorbed via oral treatment.
Parity is also known to affect the population of mammary progenitor cells, decreasing Wnt4 expression and the proliferative capability of stem cells. Full-term pregnancy early in reproductive life reduces breast cancer risk, therefore mice were bred at 3 different ages: 5, 9, and 24 weeks. After involution, mammary glands were disassociated and plated as mammospheres to study the radiation sensitivity of progenitor cells. Early pregnancy, at 5 and 9 weeks, resulted in radiation sensitivity of mammary progenitor cells that was no longer present in the mammary epithelium of mice bred at 24 weeks. Treatment of nulliparous mammospheres with Wnt4 or Sfrp1 increased the number of mammospheres relative to control. Sfrp1, a Wnt agonist, enhanced the radiation sensitivity similar to the parous mammospheres. Parity-induced alterations to the mammary gland can be used to explain and further study the protective effect against the development of breast cancer.
Karen A Dunphy
D Joseph Jerry
Majewski, Aliza, "Radiation Induces Estrogen Receptor-Mediated Genomic Surveillance to Restrict Mammary Progenitor Cell Expansion" (2018). Masters Theses. 609.