Pregnancy-related characteristics, genetic variation in estrogen-metabolizing enzymes, and maternal risk of breast cancer
Jaworowicz, David Joseph, Jr.
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Considerable evidence has accrued from in vitro , clinical, and epidemiologic studies indicating that cumulative lifetime exposure to elevated levels of circulating ovarian hormones, including estrogens and progesterone, is a significant contributing factor in breast carcinogenesis. Pregnancy represents a crucial time period that substantially impacts a woman's lifetime risk of breast cancer, with younger age at first pregnancy and multiparity conferring a protective effect on long-term risk. The exact mechanisms by which pregnancy may reduce risk have been the focus of widespread research, with considerable emphasis on the contribution of hormonal influences. Particular maternal experiences or complications in pregnancy may be indicative of altered hormonal profiles. These pregnancy-related characteristics could potentially serve as proxies for distinct hormone exposures, and provide insight into the role that estrogens may have on breast cancer risk. The goal of this doctoral dissertation project was to investigate and characterize the association between breast cancer risk and five pregnancy-related characteristics, including pregnancy-induced hypertension, preeclampsia or eclampsia/toxemia, gestational diabetes, pregnancy-associated weight gain, and pregnancy-related nausea and vomiting (NV). Given that these pregnancy-related characteristics are suspected to reflect distinct hormone profiles during and perhaps beyond pregnancy, including marked differences in estrogen exposures, we also examined genetic variation in key estrogen-metabolizing enzymes in relation to these characteristics to determine if genotype modified breast cancer risk. We evaluated a total of seven single-nucleotide polymorphisms in five genes coding for the following enzymes: cytochrome P450s CYP17, CYP1A1, and CYP1B1; catechol-O-methyltransferase; and glutathione-S-transferase P1. Overall, a total of 2,918 women with at least one reported pregnancy were included in these analyses (1,001 cases with primary, incident, histologically-confirmed breast cancer and 1,917 controls frequency matched by age and race). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models, adjusting for suspected confounders. Pregnancy-related nausea and vomiting during any pregnancy was associated with a statistically significant reduction in breast cancer risk in premenopausal (OR 0.61; 95% CI 0.42-0.90) and postmenopausal (OR 0.73; 95% CI 0.58-0.92) women. Significant and consistent inverse associations were observed with greater percentage of pregnancies in which nausea and vomiting occurred, increased NV severity, and NV lasting longer into pregnancy. These associations did not differ by estrogen receptor (ER), combined ER and progesterone receptor (ER/PR), or human epidermal growth factor receptor 2 (HER2) expression status. No significant associations with breast cancer risk were found for any of the other pregnancy-related characteristics. Carriers of the rare allele for the functional CYP1B1 rs1056836 SNP, a genotype which codes for enhanced enzyme activity, exhibited marginally positive associations with the likelihood of NV experience during pregnancy compared to common homozygous genotypes (OR1.22, 95% CI: 0.98-1.52 for the GG/GC compared to CC genotype). Significant multiplicative interactions between pregnancy-associated NV and this genotype in relation to breast cancer risk were found in both premenopausal and postmenopausal populations. While null or slightly elevated risks were observed with NV among women with the common homozygous CC genotype, statistically significant reductions in breast cancer risk were observed for those with genotypes containing the rare G allele (OR 0.54, 95% CI: 0.32-0.91 [p for interaction = 0.036] in premenopausal women and OR 0.57, 95% CI: 0.41-0.78 [p for interaction = 0.011] in postmenopausal women). The findings presented herein suggest that nausea and vomiting during pregnancy may be associated with a reduction in breast cancer risk. Although there is no evidence of independent associations between estrogen-metabolizing enzyme genotypes and breast cancer risk, there may be associations between CYP1B1 polymorphisms and NV. Effect modification by CYP1B1 rs1056836 genotype on the association between NV and breast cancer risk provides evidence of a possible mechanistic role for estrogen or its metabolites.