Environmental and genetic factors in association with breast cancer risk and tumor characteristics
MetadataShow full item record
Introduction. Research results on breast cancer etiology, especially dietary risk factors, are inconsistent. One mechanism of carcinogenesis is oxidative stress, which is closely related to the effects of dietary factors and steroid hormones. The risk of breast cancer could be impacted by the interactions between endogenous oxidative stress-related factors (i.e. antioxidant enzymes) with exogenous antioxidants (i.e. dietary antioxidants intake), as well as with reproductive histories that are highly related to lifetime hormone exposures. The inconsistency of dietary effects on risk may also be partly due to tumor heterogeneity, with different subtypes having distinct etiologies. In this dissertation, we first investigated interactions between polymorphisms in several oxidative stress-related genes and vegetable, fruit, and dietary antioxidant intake, as well as with reproductive factors, separately, on the risk of breast cancer. Then we evaluated whether dietary patterns are related to breast cancer tumor characteristics. Patients and Methods. A nested case-control study of postmenopausal women (505 cases and 502 controls) from the CPS-II nutrition cohort was conducted to examine the possible interactions. Participants were genotyped for genetic polymorphisms in CAT ( C-262T ), MPO ( G-463A ), NOS3 ( G894T ), and the HO-1 [( GT ) n dinucleotide length]. The relationships between dietary patterns and tumor characteristics were evaluated using data from a set of Caucasian American women diagnosed with invasive breast cancer at Roswell Park Cancer Institute (n=375). Principle component analysis was used to identify dietary patterns. Logistic regression models were applied in all the studies to evaluate the interactions of interest and associations between dietary patterns and tumor characteristics. Results. Genetic variations in CAT, MPO, NOS, and HO-1 were not significantly associated with breast cancer risk. When associations were examined by level of vegetable and fruit consumption, women carrying the low risk CAT CC, NOS3 TT, and the HO-1 S allele and MM genotype were found to be at non-significantly reduced breast cancer risk among those with high intake. Furthermore, those with ≥ 4 putative low risk alleles in total ( CAT C, MPO A, NOS3 T, HO-1 S and M ) had significantly reduced breast cancer risk (OR=0.53, 95% CI=0.32-0.88, p-interaction 0.006) compared to those with ≤2 low risk alleles. In contrast, among women with low vegetable and fruit intake (< median), the low risk CAT CC, NOS3 TT (OR=2.93, 95% CI=1.38-6.22), and MPO AA genotypes were associated with either non-significantly or significantly increased breast cancer risk compared to participants with ≤ 2 low risk alleles (OR=1.77, 95% CI=1.05-2.99, p-interaction 0.006). For relationships between reproductive factors and genotypes, non-significant associations were observed between age of menopause and CAT, MPO, and HO-1 genotypes. After stratification by reproductive factors, we noted inverse associations with CAT CC genotype only among women with older age at menarche (OR=0.54, 95%CI=0.30-0.97), with HO-1 S alleles or MM genotypes only among women with early menarche (OR=0.60, 95%CI=0.40-0.91) or with late menopause (OR=0.66, 95%CI=0.43-1.02). For MPO, GA or AA genotypes increased risk among those with early menarche (OR=1.61, 95%CI=1.05-2.46), and older age of first full-term pregnancy (OR=2.60, 95%CI=1.44-4.70, p-interaction0.07). Within the case-only study at RPCI, we identified three major dietary patterns (healthy, traditional, and fast food). Compared to patients with lower consumption of the healthy pattern, women who were high consumers of the healthy pattern were at decreased odds of having more aggressive tumors with later stage (OR=0.62, 95%CI=0.38-1.04), and postmenopausal estrogen receptor (ER)-positive breast tumors (OR=0.40, 95%CI=0.20-0.80), but increased risk of HER2-overexpressing subtype (OR=3.78, 95%CI=1.18-12.09) in postmenopausal women. The fast food pattern was associated with a non-significantly decreased progesterone receptor (PR)-negative tumors with PR-positive tumors as the referent, but only among postmenopausal women. Conclusions. Our results support the hypothesis that there are joint effects of endogenous and exogenous antioxidants. Hormonal factors, similarly, may also modify potential genotype effects in these pathways. Our findings support the hypothesis that breast cancer subtypes have different etiologies, and dietary data may predict breast cancer aggressiveness.