Epidemiological Study On The Relationship Of Menstrual, Reproductive Factors And Cyclooxygenase 2 Gene Polymorphisms And Breast Cancer

Partâ… A case-control study on menstrual and reproductive factorsof female breast cancer in NanjingHigh level of endogenous estrogen is believed to contribute to theetiology of breast cancer. Some endogenous estrogen exposure relatedfactors, such as menstrual and reproductive factors, as well as familyhistory of breast cancer (FHBC) may increase risk of breast cancer. Theepidemiology of breast cancer had been widely studied in differentpopulations, particularly among high-risk Caucasians, and theconclusions were inconsistent. In this study, we investigated the riskfactors of female breast cancer in Nanjing.[Objective] To study the difference of menstrual and reproductivefactors between breast cancer cases and cancer-free controls, and tofurther clarify the role and impact of menstrual and reproductive factorsin relation to breast cancer in Nanjing. [Methods] A hospital-based case-control study was conducted, andunivariate and multivariate unconditional logistic regression was used toevaluate the association of menstrual, reproductive factors and familyhistory with breast cancer risk in 505 histologically-confirmed patientswith incident breast cancer and 524 cancer-free controlsfrequency-matched for age and area in Nanjing.[Results]1. OR and 95% CI for breast cancer risk associated with menstrualcharacteristicsLate age at menarche was related to decreased risk of breast cancer,and age at menarche was inversely associated with risk of breast cancer(P for trend,＜0.001). Among menopausal women, risk of breast cancer insubjects with nonnatural menopause was significantly higher than that insubjects with natural menopause (adjusted OR=10.12, 95% CI,4.85-21.12). Accumulative menstrual years, menopausal status and age atnatural menopause were unrelated to risk of breast cancer.2. OR and 95% CI for breast cancer risk associated with reproductivecharacteristicsLogistic regression revealed that never having a live birth and nobreast-feeding history were unrelated to risk of breast cancer. However,later age at first live birth was significantly associated with risk of breastcancer. Women who had their first live birth at age 29 or older had ahigher risk of breast cancer, compared with women who had their firstlive birth at age 23 or younger (adjusted OR=1.50, 95% CI, 1.02-2.19).More numbers of live births was a protective factor, and numbers of livebirths was inversely associated with risk of breast cancer (P for trend,0.005). Moreover, the abortion history increased the risk of breast cancer,and more numbers of abortion was associated with risk of breast cancer (P for trend,＜0.001).3. OR and 95% CI for breast cancer risk associated with family historyThe distribution of family history of breast cancer in first-degreerelative in cases and controls were significantly different. The frequencyof positive FHBC in cases was 3.5%, higher than in controls (0.6%), anda significantly increased risk of breast cancer was found to be associatedwith positive FHBC (adjusted OR=6.82, 95%CI, 1.97-23.61). And familyhistory of cancer (except breast cancer) (FHC) in first-degree relative wasalso associated with the risk of breast cancer (adjusted OR=1.37, 95% CI,1.03-1.83).4. Multivariate unconditional logistic regressionMultivariate unconditional logistic regression analyses revealed thatlate age at menarche and more numbers of live births were protectivefactors, and more numbers of abortion, positive FHBC in first-degreerelative were risk factors of breast cancer.5. Stratified analysesAssociation of breast cancer with abortion history and number ofabortion was observed in both strata defined by menopausal status.However, early age at menarche, less numbers of live births, late age atfirst live birth, more numbers of abortion and never breast-feeding wereassociated with increased risk of breast cancer only amongpost-menopausal women.6. Estimation of Population attributable risk percentage (PARP)In this study population, less numbers of live births were the majorcontributors to breast cancer (PARP=23.65%). Nonnatural menopauseand abortion history also have high PARP (PARP=19.99%, 19.90%,respectively). [Conclusion] Menstrual and reproductive factors may play animportant role in the development of breast cancer among Nanjingpopulations.Partâ…¡Functional polymorphisms in the cyclooxygenase 2 (COX-2)gene and risk of breast cancer in a Chinese populationCyclooxygenas (COX), the rate-limiting enzyme in prostaglandins(PGs) synthesis, exists in at least two isoforms, COX-1 and COX-2.COX-2 plays an important role in carcinogenesis and over-expressionmay increase estrogen synthesis and proliferation, inhibit apoptosis, andenhance the invasiveness of breast cancer cells. Polymorphisms in theregulatory regions of COX-2 gene may influence function and/orexpression and contribute to interindividual variability in susceptibility tocancer. In this study, we investigated the association between geneticvariants of COX-2 and risk of breast cancer by PCR-restriction fragmentlength polymorphism (RFLP) assay.[Objective] To study the distribution of three polymorphisms(-1195G/A and-765G/C in the promoter and 8473C/T in 3'UTR) ofCOX-2 in breast cancer cases and cancer-free controls and to examinedthe association between variant genotypes of COX-2 gene andindividual's susceptibility to breast cancer in Chinese.[Methods] In this case-control study including 615 histologicallyconfirmed incident breast cancer patients and 643 cancer-free controls frequency-matched for age and area, we genotyped the two promoterpolymorphisms (-1195G/A, -765G/C) and a 3'UTR polymorphism(8473C/T) of COX-2 by PCR-RFLP method to determine theirassociation with risk of breast cancer. Genotyping was performed blindlyand 10% of the samples were randomly selected for repeated assays.Finally, a total of 601 (97.7%) cancer cases and 643 (100%) controls weresuccessfully genotyped for all three polymorphisms of COX-2. Theassociation between COX-2 variants and breast cancer risk wereestimated by computing the ORs and 95%CIs from logistic regressionanalyses.[Results]1. The distribution of genotypes of COX-2 in cancer cases and controlsThe distribution of COX-2 -1195G/A, -765 G/C and 8473C/Tgenotypes were not significantly different between cases and controls(P=0.260, 0.235 and 0.980).2. Logistic regression analyses for the associations between variantgenotypes of COX-2 and breast cancerNo overall significant associations were detected in the single locusanalysis between three polymorphisms of COX-2 and the risk of breastcancer when adjusted for age, menopausal status and BMI. However, asignificantly increased risk of breast cancer was associated with thecombined genotypes containing 'more than 3 variant alleles' (adjustedOR=1.36, 95% CI=1.01-1.83) compared with the combined genotypeswith '0-3 variant alleles'.3. Stratified analysesThe associations of three polymorphisms of COX-2 with breastcancer risk stratified by age, menopausal status, age at menarche, age atfirst live birth, numbers of live births, numbers of abortions and family history of cancer were analyzed, but no significant associations werefound. And also, we analyzed the associations of three polymorphisms ofCOX-2 with breast cancer risk stratified by breast cancer relatedphenotypes. We found that -765 GC/CC genotype significantly increasedrisk of breast cancer among ER negative subject (OR=1.70,95%CI=1.07-2.70), and also a significantly increased risk of breastcancer was associated with the combined genotypes containing 'morethan 3 variant alleles' among ER negative, PR negative and cerbB-2positive subjects respectively.4. Haplotype analysesHaplotype A_-1195G_-765T₈₄₇₃ was more common in the cancer cases(37.03%) than in controls (33.81%) (P=0.045). Compared with the mostcommon haplotype G_-1195G_-765T₈₄₇₃, the A_-1195G_-765T₈₄₇₃ haplotype wasassociated with significantly increased risks of breast cancer (OR=1.20,95%CI, 1.01-1.43).[Conclusion] These findings indicate that these three variants in theregulatory regions of COX-2 may contribute to the etiology of breastcancer, functional studies and larger studies are needed to confirm ourfindings.