CYP17 & SULT1A1 gene polymorphisms in Indian breast cancer

Background: Breast cancer is the most common cancer among women worldwide. Life-time exposure to steroid hormones, especially estrogen, is a major risk factor for breast cancer. Functional polymorphisms in genes encoding steroid metabolizing enzymes may thus be important as biomarkers of individual susceptibility to breast cancer. The CYP17 and SULT1A1 genes encode for two enzymes involved in hormone biosynthesis and metabolism. Single nucleotide polymorphisms of these genes may result in inter-individual variability in steroid hormone biosynthesis and metabolism thus influence the development of breast cancer. Methods: We tested this hypothesis by conducting a case- control study on a group of 140 breast cancer cases and 140 healthy age-matched controls. Analysis of CYP17 & SULT1A1 genotypes were done by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Results: The genetic polymorphisms of the estrogen-related genes SULT1A1 (OR=2.5, 95%CI=1.28-4.98) and CYP17 (OR=4.1, 95% CI=1.78-9.63) were associated with an increased risk of breast cancer among postmenopausal women. Our data also showed evidence for the genetic regulation of serum 17Lj estradiol (E2) levels as measured by ELISA among the premenopausal women with a significant increase in the serum E2 level for the CYP17 A2 variants. Conclusion: These results suggest that both CYP17 and SULT1A1 genotypes could be important determinants of breast cancer risk in Indian women and may help in early identification of high risk subjects. Such genotype analysis resulting in a high-risk profile holds considerable promise for individualizing screening, diagnosis and therapeutic intervention in breast cancer

Role of xenobiotic metabolizing gene polymorphisms in breast cancer susceptibility and treatment outcome

Metabolic activation and inactivation of potential genotoxic agents occur by Phase I and Phase II enzymes in multiple interactions. An expanding body of literature demonstrates that ethnic differences in breast cancer incidence may be partly caused by host genetic factors particularly genetic polymorphisms of these carcinogen-metabolizing enzymes. The present case-control study aimed at identification of such low penetrance breast cancer susceptibility genes in 224 Indian women and to investigate the potential effects of their polymorphisms on sporadic breast cancer risk. The main objective of the study was to evaluate the effects of genetic polymorphisms of the xenobiotic metabolizing genes CYP1A1, GSTM1 and GSTT1 on breast cancer risk by PCR-RFLP and DNA sequencing. Our results showed a significant association between CYP1A1 m1, m2 polymorphisms and breast cancer risk; however there was a lack of association between GSTM1 null deletion and breast cancer. The associations of CYP1A1, GSTM1 and GSTT1 genotypes with breast cancer risk were more pronounced among the pre-menopausal patients. Combined genotype analysis revealed the CYP1A1 m2 ValVal–GSTM1 homozygous null deletion genotype combinations to be associated with the highest risk of breast cancer (OR=10.3, 95%CI=1.2–86.1). Correlations with clinicopathological factors and treatment outcome were also analyzed for predicting disease free survival by univariate and multivariate analysis. Significant differences in disease free survival between the wild and polymorphic genotypes were observed only for CYP1A1 m2, GSTT1 genotypes. Our results based on the analysis of functionally relevant polymorphisms in these low penetrance genes may provide a better model that would exhibit additive effects on individual susceptibility to breast cancer. Such genotype analysis resulting in a high-risk profile holds considerable promise for individualizing screening and therapeutic intervention in breast cancer. Hence, the present study may provide strong supportive evidence for genetic interactions in the etiology of breast cancer

Polymorphisms in DNA repair gene XRCC1 and increased genetic susceptibility to breast cancer

X-ray repair cross-complementing 1 (XRCC1) gene encodes for a scaffolding protein, which plays an important role in base excision DNA repair by bringing together DNA polymerase beta, DNA ligase III and poly(ADP-Ribose) polymerase (PARP) at the site of DNA damage. Three polymorphisms of the XRCC1 gene at codons 194, 280 and 399 leading to a mino acid changes at evolutionary conserved regions are found to alter the efficiency of the resulting protein and may therefore constitute potential breast cancer risk. In the present study we sought to determine whether these genetic variants of the XRCC1 gene was associated with any increased risk of breast cancer among the South Indian women in a hospital based case control study using PCR-RFLP and DNA sequencing techniques. Our data showed a positive association between the polymorphisms of codons 194 (OR=1.98, 95% CI=1.13-3.48 for Trp allele) and 399 (OR=2.14, 95% CI=1.29-3.58 for Gln allele) and breast cancer risk. However, XRCC1 codon 280 genotype analysis showed no evidence for an association with increased risk of breast cancer. A combined analysis of the effect of XRCC1 codon 194 and 399 revealed the highest risk (OR=3.64, 95% CI=1.57-8.46) for carriers of the polymorphic alleles in both these codons. In conclusion, the present study suggested involvement of XRCC1 codon 194 and 399 polymorphisms in the genetic predisposition to breast cancer among South Indian women. Our preliminary results based on the analysis of functionally relevant polymorphisms in XRCC1 low penetrance gene may provide a better model that would exhibit additive effects on individual susceptibility to breast cancer

Transforming growth factor beta related to extent of tumor angiogenesis but not apoptosis or proliferation in breast carcinoma

Background: Recent investigations have demonstrated the clinical significance of intralesional mean vessel density (ILVD), as a marker of tumor angiogenesis. The role of growth factors in mediating angiogenesis has also been well documented. Transforming growth factor beta (TGF/β) belongs to a family of polypeptides with diverse biological functions. Very few studies however have looked at the role of this growth factor in relation to angiogenesis. This study analyzed the significance of TGFβ in relation to CD34, an endothelial cell marker, the extent of apoptosis, and tissue proliferation defined by Ki67 expression in breast cancer. Methods: The extent of apoptosis was defined by morphological criteria and the Tdt-mediated dUTP biotin nick end labelling (TUNEL) assay. Immunocyfochemistry was performed to measure TGFβ, CD34 and Ki67 expression. Results An inverse association was observed between TGFβ expression and ILVD as evident by CD34 labelling (r=-0.31182, p=0.00005). TGFβ expression did not correlate with either TUNEL reactivity or Ki67 expression. CD34 and TGFβ expression also had no relationship with histopathological grade. No correlation was observed between CD34 expression and apoptosis. However a statistically significant correlation was observed between CD34 and Ki67 expression. Conclusions: These results suggest that breast cancer cells synthesize TGFβ that, through paracrine mechanisms, may inhibit proliferation of vascular endothelium rather than their own growth Moreover the data also suggest that decreased expression of TGFβ was associated with on increase in neovascularization, which in turn would increase the tumor proliferative fraction