Transforming-growth factor β1 Leu10Pro polymorphism and breast cancer morbidity☆
Introduction
The proliferation of cancerous breast epithelial cells is regulated by different stimuli including cytokines and growth factors,1 such as the transforming-growth factor β (TGF-β). TGF-β has three isoforms TGF-β1, TGF-β2 and TGF-β3. TGF-β1 is the most abundant and universally expressed isoform.2 It is known to be expressed in endothelial tissue3 and has an effect on the growth of mammary epithelium.4 Furthermore, it has recently been suggested that TGF-β1 has a dual role in tumour growth. It acts as a tumour suppressor inhibiting epithelial cell proliferation in early stages and as a tumour promoter in later stages of carcinogenesis.5 Both activities of TGF-β have been clearly demonstrated in genetically modified mouse lines in which the TGF-β signalling pathway is ablated or modified.6 These studies imply that TGF-β isoforms inhibit the development of early, benign lesions but enhance invasion and metastasis when the tumour suppressor activity is overridden by oncogenic mutations in other pathways.7
The gene encoding for TGF-β1 is located on chromosome 19q13.1. A T29C transition that results in a Leu10Pro substitution in the signal peptide sequence in this gene has been associated with higher circulating levels of TGF-β1. Proline homozygotes have been found to have increased serum levels of TGF-β1.8, 9 This variant has been studied in relationship to the risk for breast cancer but these studies have been inconclusive.10, 11, 12, 13, 14, 15, 16, 17 The aim of this study is to examine the relationship of the Leu10Pro polymorphism and the risk of breast cancer in an association study.
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Study population
Our study population is part of the Rotterdam study18 where inhabitants of Ommoord, a suburb in Rotterdam, aged 55 or older were invited to participate and 7983 agreed to do so (response rates = 78.1%). Participants’ informed consent was obtained and the Medical Ethics Committee of the Erasmus Medical Center approved the study. Our study group comprised 4878 postmenopausal women.
Measurements
Information on risk factors such as age at menarche, age at menopause and hormone replacement therapy use (HRT) was
Results
The frequencies of the Leu10Pro genotypes of the TGF β1 gene were in Hardy–Weinberg equilibrium proportions (p = 0.98). The descriptive statistics of our study population are shown in Table 1. The distribution of these risk factors was not significantly different among genotype groups.
At baseline there were 66 prevalent postmenopausal breast cancer cases, while another 143 were diagnosed during follow-up. The prevalent cases were not included in our analyses. We did not find any statistically
Discussion
In this association study, we show a statistically significant increase in risk of breast cancer for carriers of at least one copy of the proline allele of the Leu10Pro polymorphism in the TGF-β1 gene, when compared to non-carriers in Caucasian postmenopausal women. Our research is part of the Rotterdam Study, a population based cohort study for disease determinants in the elderly. The strength of our study is based on its prospective basis but although we did find significant evidence for an
Conflict of interest statement
None declared.
Acknowledgements
A. Arias Vasquez is supported by a grant from the Centre of Medical Systems Biology, Grant # 297-2003. The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organization for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European
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A. Arias Vásquez and C. van Duijn participated in the design and writing of the manuscript. J. Witteman, A. Uitterlinden, J.W. Coebergh, B.H.Ch. Stricker and A. Hofman aided in the data collection and the writing of this manuscript as well.