Polymorphisms in the MDM2 promoter and risk of breast cancer: a case-control analysis in a Chinese population☆
Introduction
Breast cancer is the most common cancer among women worldwide, and more than 1,000,000 new cases are diagnosed every year [1]. In China, the incidence rate of breast cancer has been significantly increasing both in urban and rural areas in last three decades [2]. Although the researchers have reached a consensus that breast cancer is resulted from multiple environmental factors as well as genetic alterations, such as genetic polymorphisms [3], [4], the exact molecular mechanisms of breast cancer are still under intensive investigation.
Among the genetic alterations, the tumor suppressor protein, P53, is a principal mediator of multiple cellular functions, including growth arrest, senescence, and apoptosis in response to cellular damage [5], [6]. The activity of P53 may either be inactivated or be attenuated in a vast majority of human cancers through mutations in the P53 gene or aberrant expression of proteins acting in the P53 pathway, such as MDM2 [7].
MDM2 coded by the Murine Double Minute2 (MDM2) gene, is an important negative regulator of P53. Besides its directly inhibiting the transcriptional activity of P53, MDM2 also stimulates the nuclear export and proteolytic degradation toward P53 as an E3 ubiquitin ligase [8], [9], [10]. Overexpression of MDM2 is observed both in epithelial cells of transgenic mice with induced mammary carcinomas [11] and in multiple human tumors, including breast cancer [12], [13], [14], [15]. Jones et al. reported that massive overexpression of a full-length MDM2 cDNA in the mammary epithelium of transgenic mice inhibited normal development of the mammary gland and increased papilloma formation [16]. Furthermore, amplification of the MDM2 gene is more frequent in cancer cells with the wild-type P53 than in cells with the mutant or deleted P53, which might suggest that overexpression of MDM2 can substitute for inactivated P53 by mutation [17], [18], [19], [20].
The human MDM2 gene comprises two promoters, a constitutive promoter and a P53-response intronic promoter [21]. Recently, a novel T to G substitution located in the intronic P53-response promoter of MDM2, named SNP309, has been identified, which was found to increase the affinity of the transcriptional activator Sp1 and subsequently resulted in higher expression levels of MDM2 RNA and protein [22]. Moreover, a clinical epidemiological study showed that individuals carrying the G allele of SNP309 had a significantly earlier age of onset of both hereditary and sporadic cancers [22]. Specifically, hereditary Li–Fraumeni individuals carrying the G allele of SNP309 developed breast cancer on average 10 years earlier than those who did not [22]. Therefore, it is hypothesized that this functional variant in the MDM2 promoter may contribute to individual's susceptibility to breast cancer. In addition, in the SNP databases, we also searched for genetic variants in the MDM2 constitutive promoter and found a common 40-bp insertion/deletion polymorphism (Del1518) at −1518 position (http://egp.gs.washington.edu/), which contains a putative TATA motif.
To test the hypothesis that the functional variants in the MDM2 promoter are associated with risk of breast cancer, we conducted a molecular epidemiological study of breast cancer in a Chinese population, genotyped both SNP309 and Del1518 polymorphisms in 366 breast cancer cases, 263 BBD and 605 cancer-free controls, and evaluated the association between these two polymorphisms and breast cancer risk.
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Study subjects
This hospital-based case–control study included 629 cases with breast diseases (366 breast cancer cases, 263 patients with BBD) and 605 cancer-free controls. All subjects were genetically unrelated ethnic Han Chinese women from Nanjing City and surrounding regions in southeast China. Patients with mammary lump who underwent surgical treatment were consecutively recruited from the Cancer Hospital of Jiangsu Province, the First Affiliated Hospital of Nanjing Medical University and the Gulou
Results
The characteristics of the 366 breast cancer cases, 263 BBD patients and 605 cancer-free controls included in the analysis are summarized in Table 1. Although efforts were made to frequency match the controls (on age) to all the patients of breast diseases, the frequency matching on age between the controls and breast cancer patients as well as BBD cases was not adequate (P=0.0001 for BBD patients and P<0.0001 for breast cancer cases). In particular, BBD patients had earlier age (43.8±11.2
Discussion
In this hospital-based case–control study, we investigated, for the first time, the association between the promoter polymorphisms of MDM2 and breast cancer risk. We found that neither the SNP309 nor the Del1518+/− polymorphisms in the MDM2 gene was significantly associated with breast cancer risk in this Chinese population, suggesting that these two variants may not play a major role in the etiology of breast cancer. Moreover, our findings did not support the conclusion that the presence of G
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This work was supported in part by the National Key Basic Research Program Grants 2002CB512908, Jiangsu Natural Science Foundation BK2004145, and Postdoctoral Science Foundation of China 2004035218.