Abstract
BackgroundEstrogens are crucial tumorigenic hormones, which impact the cell growth and proliferation during breast cancer development. Estrogens are metabolized by a series of enzymes including COMT, which converts catechol estrogens into biologically non-hazardous methoxyestrogens. Several studies have also shown the relationship between estrogen and cell cycle progression through activation of CCND1 transcription.MethodsIn this study, we have investigated the independent and the combined effects of commonly occurring CCND1 (Pro241Pro, A870G) and COMT (Met108/158Val) polymorphisms to breast cancer risk in two independent Caucasian populations from Ontario (1228 breast cancer cases and 719 population controls) and Finland (728 breast cancer cases and 687 population controls). Both COMT and CCND1 polymorphisms have been previously shown to impact on the enzymatic activity of the coded proteins.ResultsHere, we have shown that the high enzymatic activity genotype of CCND1High (AA) was associated with increased breast cancer risk in both the Ontario [OR: 1.3, 95%CI (1.0–1.69)] and the Finland sample [OR: 1.4, 95%CI (1.01–1.84)]. The heterozygous COMTMedium (MetVal) and the high enzymatic activity of COMTHigh (ValVal) genotype was also associated with breast cancer risk in Ontario cases, [OR: 1.3, 95%CI (1.07–1.68)] and [OR: 1.4, 95%CI (1.07–1.81)], respectively. However, there was neither a statistically significant association nor increased trend of breast cancer risk with COMTHigh (ValVal) genotypes in the Finland cases [OR: 1.0, 95%CI (0.73–1.39)]. In the combined analysis, the higher activity alleles of the COMT and CCND1 is associated with increased breast cancer risk in both Ontario [OR: 2.22, 95%CI (1.49–3.28)] and Finland [OR: 1.73, 95%CI (1.08–2.78)] populations studied. The trend test was statistically significant in both the Ontario and Finland populations across the genotypes associated with increasing enzymatic activity.ConclusionUsing two independent Caucasian populations, we have shown a stronger combined effect of the two commonly occurring CCND1 and COMT genotypes in the context of breast cancer predisposition.
Highlights
Estrogens are crucial tumorigenic hormones, which impact the cell growth and proliferation during breast cancer development
Independent Analysis of CCND1 and Catechol-Omethyl transferase (COMT) Polymorphisms Here we have investigated the independent and combined association of CCND1 Pro241Pro and COMT Met108/ 158Val polymorphisms using a case control design from two independent populations of Ontario (1228 cases and 719 controls) and Finland (728 cases and 687 controls)
The heterozygous COMTMedium (MetVal) and the high enzymatic activity of COMTHigh (ValVal) genotype was associated with breast cancer risk in Ontario cases, with an odds ratio (OR) of 1.3, 95%CI (1.07– 1.68) and 1.4, 95%CI (1.07–1.81), respectively
Summary
Estrogens are crucial tumorigenic hormones, which impact the cell growth and proliferation during breast cancer development. Estrogens are metabolized by a series of enzymes including COMT, which converts catechol estrogens into biologically non-hazardous methoxyestrogens. Estrogen demonstrates diverse effects in humans and has a critical role in breast cancer development. Estrogen exerts its effect by simultaneously stimulating the transcription of genes, via the estrogen receptor, necessary for cell proliferation and by causing DNA damage via their catechol estrogen metabolites [1,2]. Catechol-Omethyl transferase (COMT), the phase II enzyme, catalyzes the catechol estrogens into methoxyestrogens. COMT is constitutively expressed mainly in brain, liver and kidney, and in peripheral tissue, including the epithelial cells in the ducti and lobuli of normal mammary. It has been suggested that COMTLow (Met) may have 3 to 4-fold less enzymatic activity compared to COMTHigh (Val) [9,10]
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