Role of Genetic Polymorphisms in Metastasis Suppressor Genes NME1 and MKK4 as Breast Cancer metastasis modifiers

Abstract

Breast cancer in women is a major health burden both in developed and developing countries and is the second leading cause of death in women worldwide. Although, the risk of developing breast cancer is modified by environment, lifestyle, genetics and a combination of these factors, the principal factor contributing to cancer-related deaths in cancer patients is metastasis. A class of genes, known as metastasis suppressor genes which play an important role in metastasis have been identified. Malfunction of these genes due to somatic mutation or epigenetic modulations, can influence metastatic dissemination. Genetic polymorphisms in metastatic suppressor genes like NME1 and MKK4 are not well studied in breast cancer. Given the importance of metastasis in the prognosis of breast cancer it makes sense to study such genotypes and their possible association with aggressiveness as well as prognosis of the cancer. Hence we analyzed the relationship between NME1 and MKK4 polymorphisms and breast cancer risk in Kashmir, India. newlineThe different genotypes of NME1 and MKK4 genes were analyzed by polymerase chain reaction and restriction fragment length polymorphism in 130 breast cancer cases and 200 age and sex matched controls. Conditional logistic regression models were used to assess the association of various genotypes with breast cancer. In this study we found an inverse association between MKK4 promoter polymorphism and breast cancer risk. As compared to TT (wild) genotype, individuals with TG (heterozygous) (OR=0.32; 95 % CI= (0.17- 0.58) and GG (mutant) (OR= 0.13; CI=0.04 - 0.40) genotypes showed decreased risk of breast cancer. We did not find any association between NME1variants and breast cancer risk in this study. However, when participants were classified on the basis of lymph node involvement, a strong association between NME1 heterozygous genotype (OR=3.82; CI = (1.54 - 9.44) and breast cancer was found. Hence, our study suggests inverse association of MKK4 gene with breast cancer risk and elevated risk duetoNME1