br Introduction br One of the most
One of the most common cancer in women worldwide is breast cancer (Ghoncheh et al., 2016). Studies indicated that the burden of breast cancer globally would be more than 2 million by 2030. In India, breast cancer ranks first among the incidence and number of cases of all cancers in females (Malvia et al., 2017). Worldwide, breast cancer is the major cause of morbidity and mortality (Ferlay et al., 2015). Breast cancer incidence ranges from 19.4 to 89.7 per 100,000 people in East Africa and West Europe (World Health Organization, 2015). The mor-tality rate is 12.7 per 100,000 in India. A population-based cancer
E-mail address: [email protected] (A.M. Francis).
registry has revealed that in India the diagnosis of breast cancer was made in about 80,000 women, of which the annual G-1 was 40,000. A woman's lifetime exposure to high levels of estrogen has been implicated in the predisposition of hormone-related cancers. The pos-tulated mechanism for the relation of cancer risk and the concentration of estrogen includes the ability of estrogen to promote cell growth on binding to estrogen receptor, estrogen stimulation of cell division, and increase of the genotoxic effect via oxidative damage. Menarche at early age, menopause at late age, and age at first pregnancy modulate the cancer risk through the endogenous hormone exposure (Althuis et al., 2003). Phase I metabolizing and phase II metabolizing enzymes have
Available online 17 December 2018
Factors associated with breast cancer risk.
Nulliparous 22 19
Odds ratios and 95% CI was calculated by logistic regression analysis showed association with oral contraceptive.
recently been the focus of attention due to their in-depth role in the metabolism of sex steroid hormones, chemical carcinogens, and de-toxification process, and so they play a dual role in cancer progression and therapeutic responses (Reszka et al., 2006). Phase I enzymes take part in the oxidation, reduction, and hydroxylation reaction of the substrates, forming reactive carcinogens, and phase II enzymes are implicated in detoxification and elimination process (Turesky, 2004). Thus, both the phases are implicated in breast cancer etiology. The alteration in the activity of the enzyme either increase or decrease ac-tivity and have high potential to alter the level of estrogen exposure. Functional single-nucleotide polymorphisms in genes coding for the key enzymes involved in these metabolic pathway influence cancer risk by modulating the levels of estrogen metabolites and hormone levels.
Estrogens, in addition to growth-promoting activity, can be metabo-lized to intermediates of catechol that causes lipid peroxidation, DNA damage, and DNA adducts (Sampson et al., 2016). The metabolic pathway of estrogen occurs through the hydroxylation by the CYP1B1 and CYP1A1 enzymes; 2-hydroxylation of estrogen is favored by CYP1A1, whereas 4-hydroxylation of estrogen is favored by CYP1B1 (Cribb et al., 2006; Yager and Davidson, 2006). The concentration of catechol estrogens is low in circulation as they are metabolized by con-jugation by O-methylation, and glucouronidation. Slow and incomplete clearance of hydroxylated estrogen leads to the accumulation of reactive oxygen species, promoting the development and progression of cancer (Yager and Davidson, 2006). Single nucleotide polymorphisms of mul-tiple selected genes (CYP1A1, CYP1B1and SULT1A1) are considered with main importance to genes involved in the Estrogen metabolism. Ratio-nalized on its role as functionally relevant polymorphism with biological effect. Polymorphism of the above said genes have shown to have greatest link with breast cancer and has been reported by several studies in different populations. Studies from India have shown inconsistent
results. Multi SNP studies has been carried in various population globally revealing ethnic variations. Considering the differences owing to food habits, environmental exposures life style and ethnicity it is needed to perform such multi SNP study to determine the cumulative effect of the genetic variants of the pathways implicated in breast malignancy with respect to South Indian women. The selected genes are studied for the first time in the Tamil Nadu region of southern Indian population. The polymorphisms in genes (CYP1A1, CYP1B1) of bioactivation pathway, (SULT1A1) of detoxification pathway could affect the levels of transla-tion, transcription, and activity of enzymes and result in wide inter-in-dividual differences of responses to carcinogenic substances. Thus ge-netic polymorphisms of the genes of metabolic activation and deactivation pathway of environmental toxicants and estrogens merits investigations. Identification of disease susceptibility gene in a popula-tion will lead to the identification of individuals at risk. Thus identifi-cation of epidemiological and genetic factors significantly associated with the increased or decreased risk of BC in females from different ethnic groups of India is at utmost need to combat this disease at the earliest. The selected genes also play a role in drug metabolism and thus has a dual role in cancer progression and therapeutic responses.