Untitled

Funder

Organizational Unit

Publications

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

Embargoed access

The Pros and Cons of Estrogens in Prostate Cancer: An Update with a Focus on Phytoestrogens

Publication . Figueira, Marília I; Carvalho, Tiago; Monteiro, Joana; Cardoso, Henrique J.; Correia, Sara; Vaz, CV; Duarte, Ana Paula; Socorro, Sílvia

The role of estrogens in prostate cancer (PCa) is shrouded in mystery, with its actions going from angelic to devilish. The findings by Huggins and Hodges establishing PCa as a hormone-sensitive cancer have provided the basis for using estrogens in therapy. However, despite the clinical efficacy in suppressing tumor growth and the panoply of experimental evidence describing its anticarcinogenic effects, estrogens were abolished from PCa treatment because of the adverse secondary effects. Notwithstanding, research work over the years has continued investigating the effects of estrogens, reporting their pros and cons in prostate carcinogenesis. In contrast with the beneficial therapeutic effects, many reports have implicated estrogens in the disruption of prostate cell fate and tissue homeostasis. On the other hand, epidemiological data demonstrating the lower incidence of PCa in Eastern countries associated with a higher consumption of phytoestrogens support the beneficial role of estrogens in counteracting cancer development. Many studies have investigated the effects of phytoestrogens and the underlying mechanisms of action, which may contribute to developing safe estrogen-based anti-PCa therapies. This review compiles the existing data on the anti- and protumorigenic actions of estrogens and summarizes the anticancer effects of several phytoestrogens, highlighting their promising features in PCa treatment.

2024-07-23Journal article

Open access