Person:

Colditz, Graham

Background: Recent evidence suggests a role for progesterone in breast cancer development and tumorigenesis. Progesterone exerts its effect on target cells by interacting with its receptor; thus, genetic variations, which might cause alterations in the biological function in the progesterone receptor (PGR), can potentially contribute to an individual's susceptibility to breast cancer. It has been reported that the PROGINS allele, which is in complete linkage disequilibrium with a missense substitution in exon 4 (G/T, valine→leucine, at codon 660), is associated with a decreased risk for breast cancer. Methods: Using a nested case-control study design within the Nurses' Health Study cohort, we genotyped 1252 cases and 1660 matched controls with the use of the Taqman assay. Results: We did not observe any association of breast cancer risk with carrying the G/T (Val660→Leu) polymorphism (odds ratio 1.10, 95% confidence interval 0.93–1.30). In addition, we did not observe an interaction between this allele and menopausal status and family history of breast cancer as reported previously. Conclusion: Overall, our study does not support an association between the Val660→Leu PROGINS polymorphism and breast cancer risk.

Background: Early life exposures, including diet, have been implicated in the etiology of breast cancer. Methods: A nested case-control study was conducted among participants in the Nurses' Health Study who completed a 24-item questionnaire about diet during high school. There were 843 eligible cases diagnosed between onset of study (1976) and before the return of the high school diet questionnaire (1986), who were matched 10:1 with controls on the basis of age. Results: Women who had, during adolescence, a higher consumption of eggs, vegetable fat and fiber had a lower risk of breast cancer, whereas risk of breast cancer was increased among women who consumed more butter. Conclusions: A possible association of elements of adolescent diet with risk of breast cancer is reported, but the findings require confirmation in prospective study.

We assessed the association between a glutamine repeat polymorphism in AIB1 and breast cancer risk in a case-control study (464 cases, 624 controls) nested within the Nurses' Health Study cohort. We observed no association between AIB1 genotype and breast cancer incidence, or specific tumor characteristics. These findings suggest that AIB1 repeat genotype does not influence postmenopausal breast cancer risk among Caucasian women in the general population.

While the association of a number of risk factors, such as family history and reproductive patterns, with breast cancer has been well established for many years, work in the past 10–15 years also has added substantially to our understanding of disease etiology. Contributions of particular note include the delineation of the role of endogenous and exogenous estrogens to breast cancer risk, and the discovery and quantification of risk associated with several gene mutations (e.g. BRCA1). Although it is difficult to integrate all epidemiologic data into a single biologic model, it is clear that several important components or pathways exist. Early life events probably determine both the number of susceptible breast cells at risk and whether mutations occur in these cells. High endogenous estrogens are well established as an important cause of breast cancer, and many known risk factors appear to operate through this pathway. Estrogens (and probably other growth factors) appear to accelerate the development of breast cancer at many points along the progression from early mutation to tumor metastasis, and appear to be influential at many points in a woman's life. These data now provide a basis for a number of strategies that can reduce risk of breast cancer, although some strategies represent complex decision-making. Together, the modification of nutritional and lifestyle risk factors and the judicious use of chemopreventive agents could have a major impact on breast cancer incidence. Further research is needed in many areas, but a few specific arenas are given particular mention.

Introduction: The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene with functions in cell cycle arrest, apoptosis, and repair of DNA double-strand breaks. Based on family studies, women heterozygous for mutations in the ATM gene are reported to have a fourfold to fivefold increased risk of breast cancer compared with noncarriers of the mutations, although not all studies have confirmed this association. Haplotype analysis has been suggested as an efficient method for investigating the role of common variation in the ATM gene and breast cancer. Five biallelic haplotype tagging single nucleotide polymorphisms are estimated to capture 99% of the haplotype diversity in Caucasian populations. Methods: We conducted a nested case–control study of breast cancer within the Nurses' Health Study cohort to address the role of common ATM haplotypes and breast cancer. Cases and controls were genotyped for five haplotype tagging single nucleotide polymorphisms. Haplotypes were predicted for 1309 cases and 1761 controls for which genotype information was available. Results: Six unique haplotypes were predicted in this study, five of which occur at a frequency of 5% or greater. The overall distribution of haplotypes was not significantly different between cases and controls (χ2 = 3.43, five degrees of freedom, P = 0.63). Conclusion: There was no evidence that common haplotypes of ATM are associated with breast cancer risk. Extensive single nucleotide polymorphism detection using the entire genomic sequence of ATM will be necessary to rule out less common variation in ATM and sporadic breast cancer risk.