Abstract

Breast cancer is the leading cause of death from cancer among Finnish women, but the ultimate causation of carcinogenesis still remains unclear. Reactive oxygen species (ROS) is a collective term for several types of reactive oxygen metabolites that are continuously generated in human cells mainly as by-products of aerobic respiration. ROS, including nitric oxide and its derivatives, play highly important roles in cell physiology. If ROS production exceeds the capacity of detoxification systems, principally antioxidant enzymes, oxidative stress is said to occur. This state is known to contribute to all stages of carcinogenesis.

To explore the widely unstudied role of ROS and cell redox state modulating enzymes in breast carcinomas, the extent of ROS-derived macromolecule damage and the expression of the vast majority of known antioxidant enzymes were assessed in a large series of breast carcinomas, and the results were compared to the patients' clinicopathological parameters. The results were also compared to angiogenesis, DNA repair enzymes, cell proliferation, NF-κB, p53 expression, and survival. Immunohistochemistry was the main method applied, but western blotting and immunoelectron microscopy were also used.

There is extensive oxidative damage in breast carcinomas, which seems to associate with tumor development. Oxidative macromolecule damage is notable even in stage I tumors. Cell redox state regulating enzymes, such as peroxiredoxin V, thioredoxin, thioredoxin reductase, and glutamate-cysteine ligase, associate with more aggressive phenotypes of tumors, including larger primary tumors, growth of metastases, increased cell proliferation, and poor differentiation. This indirectly suggests that cell redox state modulating enzymes may be inductive of tumor promotion in an oxidated environment. The results of this thesis support the importance of ROS in all stages of carcinogenesis. These observations are largely in line with the previous studies on different carcinomas, but there seem to be certain carcinoma type specific differences in the expression of these enzymes. Since the expression of given cell redox state modulating enzymes distinctly associates with clinicopathological parameters, these enzymes may be useful as prognostic indicators and facilitate the choice of appropriate treatment in the future.