Genetic Polymorphisms of NRF2-KEAP1 and Protein Expression in Breast Cancer: a marker for prognosis and treatment.

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Genetic Polymorphisms of NRF2-KEAP1 in Breast Cancer: a marker for prognosis and treatment

Publication . Almeida, Micaela Carina Pereira; Granadeiro, Luiza Augusta Tereza Gil Breitenfeld; Patrício, Ana Cristina Monteiro Ramalhinho Tavares; Oliveira, António José Polónia Rodrigues de

Breast cancer remains the oncological disease with the greatest impact on morbidity and mortality in women worldwide. Prolonged exposure to estrogens is considered one of the main risk factors for breast cancer. This carcinogenic process is potentiated by genetic alterations in lowpenetrance genes in the estrogen biosynthetic and metabolic pathways. Phase II enzymes responsible for estrogens detoxification, are regulated by the NRF2- KEAP1 (nuclear factor erythroid 2-related factor 2 - kelch-like ECH-associated protein 1) complex. The value of this complex in estrogen detoxification led us to the aim of this thesis, which is to validate the NRF2-KEAP1 complex as a marker for breast cancer prognosis and therapy. Thus, we studied the influence of genetic polymorphisms, in low penetrance genes of the estrogen metabolic pathway in breast cancer development. The genotype of Val432Leu, C677T and null polymorphisms, respectively of CYP1B1, MTHFR, GSTM1 and GSTT1 genes, were assessed in women with hormone-dependent breast cancer. It was verified that carriers of the null genotype of GSTT1, alone or in association with the null genotype of GSTM1, as well as carriers of Val432 of CYP1B1 and the null polymorphism of GSTT1 or GSTM1, and carriers of the null genotype of GSTT1 and the T allele of the C677T polymorphism, were diagnosed with breast cancer at the age of 50 or over. The results indicate that polymorphisms that contribute to inefficient estrogen detoxification may predispose women to developing hormone-dependent breast cancer at a later age. In order to assess the clinical influence of the NRF2 rs35652124, rs6706649, rs6721961 polymorphisms and the KEAP1 rs1048290 polymorphism in breast cancer cases with a "present" GSTM1 genotype, a technique was optimised which made it possible to distinguish heterozygous from present genotypes. Heterozygous GSTM1 cases cumulatively carriers of the NRF2 and/or KEAP1 polymorphisms were associated with HER2+ (epidermal growth factor receptor 2 positive) breast cancers. There are several studies correlating NRF2 polymorphisms and its expression with breast cancer prognosis. After a systematic review with meta-analysis, it was found that patients with NRF2 over-expression had lower overall survival and shorter disease-free survival. Subsequently, the genotypes of the aforementioned KEAP1 and NRF2 polymorphisms were assessed in blood, tumour’s benign surrounding tissue and tumour tissue. There was a trend towards the loss of heterozygosity in the benign surrounding tissue and a greater variability of genotypes in histological grade 2. The acquisition of somatic mutations and their different distribution are probably the result of a more active and heterogeneous microenvironment. Polymorphisms that compromise the availability of NRF2 in the nucleus impair estrogen detoxification and may predispose to the development of postmenopausal breast cancer. High levels of NRF2 in the nucleus promote high detoxification, protecting both healthy and tumour cells. It is therefore pertinent to carry out further studies in benign and tumour tissue, in different subgroups of participants, in order to understand the role of the complex in the development and progression of breast cancer.

2025-01-27Doctoral thesis

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