Deleterious MnSOD signals lead to abnormal breast cell proliferation by radiation and estrogen exposure.

Manganese superoxide dismutase (MnSOD) seems to have a pivotal role in maintaining the normal phenotype by suppressing cell growth through blocking the entrance of quiescent cells into the cell cycle. MnSOD protein expression has been shown to be dysregulated in malignant cells. A well-established experimental breast epithelial cell cancer model was used to observe the relationship in the presence or absence of such protein and the phenotype of the cells. This model was derived from the spontaneously immortalized breast epithelial cell line MCF-10F, which was transformed with estrogen and radiation. The results of this study showed that deleterious expression of MnSOD enhanced the malignant phenotype demonstrated by cell cycle protein expression changes. Thus, the malignant cell line, called Alpha5, which had high levels of MnSOD protein expression, maintained a similar phenotype to the normal cell line MCF-10F. The cell cycle arrest observed in G1 phase of the Alpha5 cell line was induced by p16 protein expression which has been shown to inhibit the Cyclin D1/CdK4 complex explaining such arrest. It can be concluded from these studies that SOD expression, played a critical role in free radical detoxification and it is directly correlated with the cell cycle, defining one of the most important characteristics of tumor cells, namely cell growth and proliferation. These findings are in agreement with the hypothesis that MnSOD plays a role as a possible tumor suppressor gene. Furthermore, this work is a contribution to understanding the possible changes that occur in α-particle irradiated cells, sensitized with estrogen, due to the presence of superoxide dismutase scavenger that could have significant implications in the design of clinical radiotherapeutic protocols.