Influence of Estrogenic Metabolic Pathway Genes Polymorphisms on Postmenopausal Breast Cancer Risk.

Micaela Almeida,Mafalda Soares,Ana Cristina Ramalhinho,José Fonseca-Moutinho,Luiza Breitenfeld

doi:10.3390/ph14020094

Micaela Almeida, Mafalda Soares + Show 3 more

Open Access

https://doi.org/10.3390/ph14020094

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Abstract

Estrogen metabolism plays an important role in tumor initiation and development. Lifetime exposure to high estrogens levels and deregulation of enzymes involved in estrogen biosynthetic and metabolic pathway are considered risk factors for breast cancer. The present study aimed to evaluate the impact of mutations acquisition during the lifetime in low penetrance genes that codify enzymes responsible for estrogen detoxification. Genotype analysis of GSTM1 and GSTT1 null polymorphisms, CYP1B1 Val432Leu and MTHFR C677T polymorphisms was performed in 157 samples of women with hormone-dependent breast cancer and correlated with the age at diagnosis. The majority of patients with GSTT1 null genotype and with both GSTM1 and GSTT1 null genotypes were 50 years old or more at the diagnosis (p-value = 0.021 and 0.018, respectively). Older women with GSTM1 null genotype were also carriers of the CYP1B1Val allele (p-value = 0.012). As well, GSTT1 null and CYP1B1Val genotypes were correlated with diagnosis at later ages (p-value = 0.022). Similar results were found associating MTHFR C677T and GSTT1 null polymorphism (p-value = 0.034). Our results suggest that estrogen metabolic pathway polymorphisms constitute a factor to be considered simultaneously with models for breast cancer risk assessment.

Highlights

Breast cancer is the most common cancer in women, counting 2.1 million cases diagnosed in 2018 [1]
GSTT1 null genotype and GSTM1 present genotype were diagnosed at ages equal to or greater than 50 years old, and 29 of the 32 cases with both null genotypes were identified in patients at later ages
Among the 32 patients with both null genotype of GSTT1 and altered allele of methylenetetrahydrofolate reductase (MTHFR), only 2 patients were diagnosed with breast cancer before 50 years old

Summary

Introduction

Breast cancer is the most common cancer in women, counting 2.1 million cases diagnosed in 2018 [1]. 5-methyltetrahydrofolate, which allows the remethylation of homocysteine to methionof In this regard, for COMT catalyzed reactions, which allow inactivation of catechol estrogens [12]. The presence of the homozygous null polymorphisms results in the total absence of the enzymes’ activity; in estrogen metabolism, it will compromise the detoxification of catechol estrogens, known to contribute to hormone-induced carcinogenesis through DNA adducts formation [3,19,20]. The polymorphism Val432Leu (CYP1B1) increases CYP1B1 activity, contributing to higher levels of catechol estrogens that are detoxified by Phase II enzymes. C677T polymorphism of MTHFR possibly affects 4-OH-E2 catalyzation by COMT; in addition, the total absence of GSTM1 and GSTT1, due to the null polymorphisms, will highly compromise the detoxification of catechol estrogens. The present study was designed to investigate the impact of mutations acquisition in low penetrance genes during the lifetime in breast cancer development—the impact of the null polymorphisms in GSTM1 and GSTT1 in breast cancer development at later ages

Results

Discussion

Study Population

Genotyping

CYP1B1

Statistical Analysis