ROLE OF AKR1B1 IN TUMOR AGGRESSIVENESS AND ITS INTERPLAY WITH THE P53 PATHWAY IN BREAST CANCER

BORINI ETICHETTI, CARLA M.; GIRARDINI JAVIER E; BICCIATO, SILVIO; DI BENEDETTO CAROLINA; MENACHO MARQUEZ, MAURICIO

Parana

Congreso; LIV Reunion Anual SAIB; 2018

SAIB

AKR1B1 belongs to a superfamily of aldose reductases, and catalyzes conversion of aldehydes to alcohols. It has been proposed that through this activity AKR1B1 may affect different aspects of cell metabolism thereby conditioning tumor progression. However, its function in cancer is not fully understood, and some evidences are contradictory. For example, AKR1B1 was found to be hypermethylated in breast cancer patients, suggesting that it may play a tumor suppressive role. In contrast, it has been shown to promote migration and EMT in triple negative cell lines. To understand the effect of AKR1B1 in breast cancer we studied the consequences of its downregulation and overexpression on migration and invasion in vitro. We also analyzed the role of AKR1B1 on cell survival and EMT. By studying the effect of the enzyme on xylose reduction and prostaglandin F2a synthesis we explored the effects on cell metabolism. To analyze the effect of AKR1B1 on tumorigenesis and metastatic potential in vivo, we used a model of orthotopic transplantation in immunocompetent mice. By performing qPCR, luciferase assays and western blot we showed that different members of the p53 family affect AKR1B1 expression. In order to understand the clinical impact of our findings we analyzed breast cancer databases. We searched for correlations between AKR1B1 expression levels and p53 status. We also analyzed the impact of AK1B1 levels on clinical outcome. In summary, we provide novel data on the role of AK1B1 on tumor-associated phenotypes and we found a novel link between AKR1B1 expression and the p53 family that may help to understand the complex role of this enzyme in breast cancer.