Cooperative Effects of Tumor Suppressor Genes and Oncogenes on the Dynamic Process of Tumorigenesis

Abstract

The overall hypothesis of this dissertation was that certain mutations or altered proteins would have a greater tumorigenic effect if acting cooperatively rather than independently. Three studies were conducted in support of this hypothesis.

The first study evaluated cooperative interactions between Brca2 and p53. The effects of mutation of these genes on cell proliferation and apoptosis were evaluated in the developing mouse mammary gland with and without exposure to irradiation. The hypothesis was that combined mutation of both genes would produce a more deleterious response than mutation of either gene alone. Results demonstrated that individual mutation of Brca2 or p53 could alter apoptosis and/or cell proliferation but had little effect on the growth index (apoptosis:proliferation ratio). Combined mutation of both genes did alter the growth index, but only in response to irradiation.

The second study evaluated spontaneous, ethylene oxide-, and benzene-induced mouse mammary tumors for p53 and H-ras mutations. The hypothesis was that both p53 and H-ras mutations would commonly occur together in the chemically induced tumors but not in spontaneous tumors. Results revealed that p53 and H-ras mutations were common events in both chemically induced and spontaneous mammary tumors. Overall, the results revealed that cooperative interaction between these genes is important in the genesis of mouse mammary tumors in general.

The third study evaluated the protein expression of four cell adhesion molecules (KAI1, CD9, E-cadherin, and N-cadherin) in ovarian epithelial carcinomas and metastases. The hypothesis was that more than one but not all of these adhesion molecules would be downregulated as tumors progressed towards a metastatic phenotype. Results revealed the remarkable complexity of adhesion molecule modulation during metastasis and suggested that cooperative interaction is an important event in the metastatic process.

In conclusion, this dissertation evaluated cooperative interactions between several different classes of cancer-related genes and proteins and provided support for the hypothesis that particular mutations or altered proteins would have a greater tumorigenic effect if acting cooperatively rather than independently.