Dissertation Details

Dissertation Code :  IDpq 9724988

Dissertation Title   :  Involvement of matrix metalloproteinases in reproductive and carcinogenic processes


About This Dissertation

209 pages
Ph.D. dissertation
1997.

Abstract
Degradation and remodeling of the cell matrix in both normal and pathological states can be affected by a variety of enzymatic activities. The matrix metalloproteinases (MMPs) are believed to be the primary contributors to these processes.
Due to their degradative effects on the extracellular matrix, the MMPs have been associated with the restructuring of endometrial tissue that occurs during the menstrual cycle and postpartum uterine involution. Expression of MMPs during the human menstrual cycle has been correlated with low levels of progesterone, implying negative regulation of MMP expression. I have used the monkey endometrium to reveal that MMP expression levels are reduced following menstruation, independent of progesterone addition. I have also observed in the murine involuting uterus that expression of a few MMPs are upregulated in response to removing one specific MMP by homologous recombination, suggesting that these MMPs may play an important role in the involution process.
The distinct expression pattern of matrilysin (MAT), the only known epithelially expressed MMP, suggests a distinct role for this enzyme during normal and pathological conditions. I have shown that overexpression of MAT in the male reproductive tract induces decreased fertility secondary to testicular modifications, and in the female mammary epithelial cells, MAT induces premature expression of milk proteins.
Correlation between MMP expression and an increase in the ability of tumor cells to invade the basement membrane suggests that MMPs play a role in the acquisition of a metastatic phenotype. We have examined MAT overexpression in mammary tumorigenesis using a transgenic mouse model system. Surprisingly, our model system demonstrates that MAT may play a larger role in the onset of mammary tumorigenesis than in the metastasis of the primary tumor.
This research has enhanced our understanding of the regulation of MMPs in the uterine environment and has suggested the possibility for potential new substrates, such as growth factors and cytokines, for the MMP enzymes, identifying new roles for this family of proteinases in the development of cancer. The discovery of MMP substrates other than ECM components will expand the possible roles for MMPs in both normal and pathological processes.


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