Efectos de los Estrógenos, la Genisteína y la Leptina sobre el Estrés Oxidativo en el Cáncer de Mama. Importancia de la UCP2

Abstract

Oxidative stress is an imbalance between free radical production and the antioxidant systems responsible for counteracting them. The result of this imbalance is accumulation of damage in several cellular structures, including DNA. Cancer is associated with increased oxidative stress, therefore, many therapeutic treatments are targeted to raise cytotoxic ROS levels, which would lead to tumor cell apoptosis. However, during tumorigenesis, cells acquire several features that maintain ROS homeostasis and develop resistance to anticancer treatments. Breast cancer is a type of neoplasia in which the endocrine factor plays an important role in etiology and disease progress. In the preset thesis we set out to study the effects of hormonal factors: 17β-estradiol (E2), genistein and leptin, on oxidative stress modulation in breast carcinogenesis. E2 is one of the main risk factors for breast cancer initiation and progression; genistein is one of the phytoestrogens with greater estrogenic activity and, while, leptin has also shown enhancing effects on breast cancer, epidemiologically it is also considered to be a possible link between obesity and cancer. The aim of this work was to study: i) the dual effect of E2 and genistein on oxidative stress depending on the ERα and ERβ ratio in breast cancer cell lines (MCF-7 and T47D), and oxidative stress in invasive ductal carcinoma samples depending on estrogen receptor ratio; ii) the influence of chronic leptin on oxidative stress and response to anticancer drug cisplatin in MCF-7 cell line; iii) the significance of UCP2 in the regulation of endogenous and induced oxidative stress in MCF-7 cells as well as in mutant p53 pancreatic cancer cell lines. Results indicate that E2 induces oxidative stress in a ERα/ERβ ratio-dependent manner. Thus, the increase in oxidative stress, due to in part to a decrease in antioxidant systems, is mediated by ERα. In contrast, ERβ activation by genistein involves a lower oxidative stress and better mitochondrial function, which is promoted by an antioxidant response. In agreement with the in vitro study, breast tumors with a lower ERα/ERβ ratio showed a higher detoxifying response, which also improved cellular survival. In turn, leptin appears to decrease the basal level of oxidative stress, which could play a role in the acquisition of resistance to anticancer treatments. UCP2-mediated mitochondrial uncoupling protects the cancer cell from oxidative damage, which may possibly confer cytoprotection through chemoresistance acquisition. In pancreatic cancer cells, p53 mutant induces ROS production due to a decrease in UCP2, contributing to cell growth. In conclusion, the results of this thesis suggest that both ERβ and UCP2 may be interesting biomarkers for a better characterization of the tumor in relation to its level of oxidative stress and possible treatment response.