IMPLICATION OF P53 MUTATION IN THE DYSREGULATION OF METABOLIC, APOPTOTIC AND OXIDANT/ANTIOXIDANT EQUILIBRIUM IN BREAST CANCER

Abstract

Breast cancer is the most worldwide frequent invasive tumor diagnosed in women. No single genomic or metabolic condition can be regarded as decisive for its progression. Whoever, few key players can be pointed out among them the tumor suppressor p53, one of the most frequent mutated gene in human malignances. The current study aimed to explore the influence of p53 mutation in the regulation of metabolic, apoptotic and oxidant/antioxidant pathways in breast cancer. In the present study, tumor specimens were obtained from 40 women in different grades of primary breast carcinoma. Another 10 non-malignant (marginal) breast tissue samples were used as controls. Both mutant p53 (mutp53) and Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) proteins were assessed by Western blotting, while the mRNA levels of both the proapoptotic caspase-3 and the antiapoptotic Bcl-2 were assessed by RT-PCR. The breast tissue levels of MDA, NO and GSH besides SOD activity were assayed calorimetrically. Results: Our results revealed that the tumor associated mutp53 over-expression is accompanied on the one hand by Bcl-2 up-regulation and caspase-3 down-regulation reflecting a dysfunctional apoptosis. On the other hand, excessive mutp53 was associated with GAPDH redundant-expression indicating an increased glycolysis. Significant disruptions in the oxidant/antioxidant balance were also coincided with tumor-inherent p53 mutation. Conclusion: Our findings concluded that p53 mutation in breast cancer could not only perturb the tumor suppressive potential of the wild type p53 (wtp53) but also could induce dominant-negative effects over its apoptotic and metabolic functions besides its endeavor in oxidant/antioxidant equilibrium. This overview could have valuable clinical applications in establishing novel strategies for cancer therapy.