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High-density lipoprotein, advanced glycation endproducts and oxysterols in breast cancer - association with the molecular classification of tumor and disease prognosis

Grant number: 19/18431-4
Support type:Regular Research Grants
Duration: July 01, 2020 - June 30, 2022
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Marisa Passarelli
Grantee:Marisa Passarelli
Home Institution: Universidade Nove de Julho (UNINOVE). Campus Vergueiro. São Paulo , SP, Brazil

Abstract

The etiopathogenesis of breast cancer is diverse and the molecular classification of tumors and the calculation of recurrence score are used as basis for prognosis and therapeutic choice. High density lipoproteins (HDL) are inversely associated with tumor genesis by modulating the lipid content required for tumor replication, adhesion and migration, and performing antioxidant and anti-inflammatory functions. Advanced glycation products (AGEs), formed in due to increased glycolytic pathway through metabolic convergence and inflammation, are prevalent in many tumors and are associated with breast cancer prognosis. The AGE receptor (RAGE) is also related to tumor evolution, although their soluble isoforms may counteract the deleterious effects of AGEs. AGEs increase glycoxidation and disrupt lipid homeostasis, in part, by lowering the content of the HDL receptor, ABCA-1. This impairs the removal of cell cholesterol, favoring the intracellular accumulation of oxysterols, which are linked to the growth potential and metastasis of some breast tumors. In addition, HDL particles, regardless of HDL cholesterol, may potentially contribute to tumor development by modulating lipid content in the tumor cell and by its antioxidant and anti-inflammatory functions. The objective of this project is to evaluate, in women newly diagnosed with breast cancer: a) the association between the concentration of AGEs and their detoxification components (glyoxalase 1 and soluble AGE receptor); plasma oxysterols and gene expression of AGE-RAGE axis with the prognosis of the disease, according to its molecular classification, b) the concentration of oxysterols in the subfractions of high density lipoproteins (HDL2 and HDL3) and their ability remove cellular cholesterol and inhibit oxidation. Female patients, between 18 and 80 years of age (n = 100), with a recent diagnosis of breast cancer, virgins of treatment and with the molecular classification of the tumor staging from I to III will be included in the study. Healthy women in the same age group, matched for age and body mass index will be included as control group (n = 100). Concentrations of AGEs, soluble AGE receptor isoform and glyoxalase 1 will be determined in plasma by ELISA, oxysterols in plasma and in HDL2 and HDL3, by mass spectrometry. Gene expression of the AGE-RAGE axis will be determined by RT-qPCR in PBMC. These parameters will be associated with the prognosis of the tumor, inferred by its molecular classification. In addition, HDL subfractions will be tested for its ability to remove cell cholesterol and inhibit oxidation and inflammation. The results will be important in determining whether circulating AGEs and oxysterols can be used to predict breast cancer outcome in association with its molecular classification; as weel as information on HDL functionality which can modulate the disease progression. (AU)

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