Original articleEpidemiologicalSingle Nucleotide Polymorphisms in the Hypoxia-inducible Factor-1α (HIF-1α) Gene in Human Sporadic Breast Cancer
Introduction
Breast cancer is the most prevalent cancer type in the world today due to its high incidence rate and relatively good prognosis (1). Although, there are several well-established risk factors identified for breast cancer such as the inherited genetic predisposition, age of menarche and menopause, reproductive history, body mass index (BMI), prolonged use of oral contraceptives and hormone replacement therapy, and alcohol consumption, the etiology of breast cancer is still not fully understood 2, 3.
Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of cellular response to hypoxia and has been suggested to play an important role in tumor progression and metastasis through activation of >60 target genes that are particularly involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion 4, 5, 6. HIF-1α protein levels and transcriptional activity are tightly regulated in response to oxygen levels (7). HIF-1α is overexpressed in human cancers as a result of intratumoral hypoxia as well as genetic alterations (6). Experimental evidence has indicated an important role for HIF-dependent gene expression in tumor growth (4). Tumors derived from cells lacking HIF-1α or HIF-1β, a constitutively expressed subunit of HIF-1 gene, show significantly reduced vascularization and in most studies, reduced growth rates compared to parental cells 4, 8. Indeed, a large number of clinicopathological studies confirm that HIF-1α is overexpressed in the cytoplasm and nuclei of 40–80% of human carcinoma cases, including head-neck, colon, breast, stomach, pancreas, prostate, kidney, esophagus, endometrial, and non-small cell lung cancer 9, 10, 11, 12, 13. This makes HIF-1α an attractive target for the development of anticancer agents (14).
Genetic polymorphisms are responsible for interindividual variation and diversity and have been considered as the main genetic elements involved in the development of common and complex diseases (15). Single nucleotide polymorphisms (SNPs) are commonly one of the genetic alterations. Yamada et al. (16) examined all regions of the HIF-1α and found a total of 35 SNPs in the gene. Polymorphisms of the gene have not been associated with some diseases (17); however, other diseases have been associated with production of HIF1 protein and reported to be involved in susceptibility to several disorders (16). In addition, a number of studies have reported associations between HIF-1α gene polymorphisms and several types of cancer like non-small cell lung (18), head and neck 18, 19, renal cell carcinoma (20), androgen-independent prostate (21), colorectal (22), and cervical and endometrial cancers (23). On the other hand, there are many studies reporting an association between genetic polymorphisms and susceptibility to breast cancer. Gerger et al. (24) studied a comprehensive panel of genetic polymorphisms with breast cancer risk. These polymorphisms were involved in a variety of cancer-related pathways including folate metabolism (MTHFR), inflammation (IL10), angiogenesis (VEGF), cell proliferation and apoptosis (CCND1, FAS, FASL, TGFB1), cellular signaling (GNB3, ITGA2, ITGB3), degradation of extracellular matrix (MMP1 and MMP3), prostaglandin synthesis (PTGS2), and detoxification of compounds (SULT1A1) (24). Krippl et al. found that carriers of the VEGF 936T allele were less frequent in breast cancer patients than in healthy subjects, indicating that this genetic variant may be protective against breast cancer (25). In addition, Balasubramanian et al. discussed the possible role of angiogenesis-related polymorphisms in various cancer types including breast cancer in their review (26). It has been shown that a SNP at codon 388 of fibroblast growth factor receptor 4 (FGFR4) genes may predispose breast cancer patients for significantly accelerated disease progression (27). Furthermore, this polymorphism is a marker for breast cancer progression in patients with adjuvant systemic therapy, particularly chemotherapy, and thus may indicate therapy resistance (28). In another study it has been suggested that the presence of the 5A polymorphism at the MMP3 promoter may be one of the risk factors for the development and/or progression of cancer, especially in mammary tumors (29). Genetic variation in tumor necrosis factor-α (TNF-α) and heat-shock proteins (hsp70–2), determining factors in the immune response to tumor cells, may represent not only markers for the increased risk of breast carcinoma but also may predict the clinical outcome (30). TNF receptor II polymorphisms may also predict the late onset of breast carcinoma, relapse and death for patients with breast carcinoma (31). On the other hand, plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter polymorphism has not been associated with appearance and/or progression of breast cancer (32).
Although HIF-1α plays pivotal roles in the development and progression of several cancer types including breast cancer (33), there has been only one published study so far (34) regarding the relationship between HIF-1α polymorphisms and breast cancer. Therefore, in the present study we investigated the association of three SNPs, which were located in coding regions of the gene—one in exon 2 (S28Y) and two in exon 12—(P582S, A588T) with sporadic breast cancer in the Turkish population.
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Study Population
One hundred and two women (mean age 46.6 years; range, 25–65 years) for whom the existence of sporadic breast carcinoma has been histopathologically confirmed were enrolled in the study from June 2005 to January 2007. All patients came from the Departments of General Surgery, Faculty of Medicine, Gazi University and Polyclinic of Second General Surgery, Ankara Oncology Education and Research Hospital. We studied 102 consecutive healthy female (mean age 45.5 years; range, 29–60 years) blood
Results
All three SNP (C1772T, G1790A, C111A) genotype frequencies in both sporadic breast cancer patients and controls were in agreement with Hardy-Weinberg equilibrium (p >0.05). The baseline clinical characteristics of patients and controls are summarized in Table 1. There were no significant differences between patients and controls in terms of age at enrollment, age of menarche and first delivery, number of full-term pregnancies, body mass index, family history of breast and ovarian cancers,
Discussion
Breast cancer is a multifactorial disease involving a complex interplay between genetic and environmental factors. There are many association studies between SNPs and breast cancer due to the polygenic model of breast cancer susceptibility. Genes involved in angiogenesis and hypoxias are suitable candidates for possible breast cancer susceptibility genes. Our study is the first to investigate whether HIF-1α-related polymorphisms play a role in sporadic breast cancer in the Turkish population.
In
Acknowledgments
This study was supported by Gazi University Research Fund (code no. 01/2005–18).
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