Tumour modifier genes in murine models of breast and endometrial cancer

Genetically engineered mouse models of human cancer have become increasingly important tools for the study of the genetic basis of cancer development. The utility of these tools depends on the accuracy with which they model the human disease and the inherent similarities and differences between mouse and human physiology and pathology. The work described in this thesis provides a detailed characterization of the morphologic and cellular changes in normal cycling murine uterus as a function of both the estrous cycle and serum levels of 17beta-estradiol (E2) and progesterone (P4). Additionally, the effects of two potential tumour modifier genes, insulin-like growth factor 2 ( igf2) and tissue inhibitor of metalloproteinase 3 (timp3 ), were assessed in models of breast and endometrial cancer.; In general, the stage of estrous was associated with changes in epithelial cells, extracellular matrix and inflammatory cells, whereas E2 levels correlated with cellular turnover but showed fewer correlations with matrix changes. P4 levels showed the least number of correlations with these parameters, even though cyclical changes in murine mammary gland have been shown to correlate mostly with changing P4 levels.; The effect of TIMP3 deficiency on tumourigenesis was determined in two models of breast cancer and one model of endometrial cancer using timp3-/- mice. In one mammary model timp3 -/- mice showed a significant delay in tumour growth at early stages, but later their tumours caught up to those in wildtype mice. In another model, timp3-/- mice showed marked tumour suppression compared to wildtype mice in terms of tumour incidence and latency, and background mammary hyperplasia was lower in timp3 -/- mice. In contrast, timp3 -/- mice had significantly more preneoplastic lesions in an endometrial cancer model. The effect of IGF2 overexpression was also assessed in a model of mammary and endometrial tumourigenesis and there were no significant differences between IGF2 transgenic mice and wildtype mice in either organ.; In summary, this work presents a comprehensive analysis of natural hormone-uterine dynamics in the mouse, revealing the separate effects of estrous stage and hormone levels, and provides evidence that timp3 acts as a tumour modifier gene with opposing effects on mammary and endometrial tumourigenesis.