Functional Phe31Ile polymorphism in Aurora A and risk of breast carcinoma
Tong Sun,
Xiaoping Miao,
Jinwei Wang1,
Wen Tan,
Yifeng Zhou,
Chunyuan Yu and
Dongxin Lin2
Department of Etiology and Carcinogenesis and 1 Department of Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
2 To whom correspondence should be addressed. Tel: +86 10 677 22460; Fax: +86 10 677 13359; Email: dlin{at}public.bta.net.cn
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Abstract
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Aurora-A/BTAK/STK15, involved in regulating centrosomes and chromosome segregation, is overexpressed in human breast carcinoma and other cancers. The Phe31
Ile polymorphism in Aurora A alters the kinase function, with the Ile31 variant being preferentially amplified and associated with degree of aneuploidy in human tumors. We have previously shown that the Phe31Ile polymorphism is associated with the occurrence and advanced disease status of esophageal cancer. This casecontrol study examined the contribution of this polymorphism to susceptibility to development and progression of breast cancer. Aurora A genotypes were determined in 520 patients with breast carcinoma, 191 patients with benign breast diseases (BBD) and 520 controls. It was found that the Aurora A Ile/Ile genotype was significantly associated with increased risk of breast carcinoma occurrence [odds ratio (OR) 1.66; 95% confidence interval (95% CI) 1.292.12] compared with the Phe/Phe or Phe/Ile genotype. The increased risk for BBD and breast carcinoma related to the Ile/Ile genotype was more pronounced in younger subjects. Moreover, we found that patients carrying the Ile/Ile genotype tended to have ERcarcinomas (OR 2.56; 95% CI 1.245.26). No significant association was observed between the polymorphism and metastasis and disease stage of the cancer. These findings suggest that the Phe31Ile polymorphism in Aurora A may be a genetic modifier for developing breast carcinoma.
Abbreviations: BBD, benign breast disease; CI, confidence interval; ER, estrogen receptor; OR, odds ratio; PR, progesterone receptor
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Introduction
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The hallmark of most cancers is genetic instability, which can be caused by specific gene mutations and acquired aneuploidy (1). Centrosomes maintain genomic stability by establishing the bipolar spindles during cell division and accurate segregation of the chromosomes during mitosis. Defects in centrosome number, organization and behavior constitute a condition defined as centrosome amplification, which is an important character of some breast cancers and other solid tumors in general. Centrosome defects have been suggested to play a role during neoplastic transformation by increasing the incidence of multipolar mitoses and related spindle abnormalities and aneuploidy (2,3). Aneuploidy is thought to be one of the earliest steps in tumor formation (4). Although a direct link between defects in the mitotic apparatus and aneuploidy in cancer remains to be fully elucidated, a serine/theonine kinase, Aurora A (also known as STK15, BTAK and AIKI), has been shown to play an important role in chromosome segregation and centrosome functions (5,6). Aurora A, the gene encoding this kinase, maps to 20q13.2, a region that is frequently amplified in a number of cancer cell lines and primary tumor types (79). Previous studies have shown that amplification or ectopic expression of Aurora A in mammalian cells causes centrosome dysfunction, chromosome instability and tumorigenic transformation, suggesting that Aurora A may play a central role in these oncogenic processes (1012).
Aurora A has been shown to be overexpressed in many human tumors, noticeably in breast cancer, even without gene amplification (7,1315). It has been demonstrated that elevated expression of Aurora A is associated with centrosome anomalies and aneuploidy and is an early event in breast carcinogenesis (16,17). In addition, expression of Aurora A has been shown to be influenced by sex steroid hormones such as estrogen (18), an established risk factor for breast cancer (19), and simultaneous existence of hormone stimulation and overexpression of Aurora A may accelerate experimental mammary tumorigenesis (17). All of these data indicate an important role of Aurora A in the development of breast cancer.
A single nucleotide polymorphism (T91A) has been identified in the coding region of Aurora A, which causes a Phe31
Ile amino acid substitution (20). It has been shown that, compared with the Phe allele, the Ile allele is preferentially amplified and associated with a degree of aneuploidy in human tumors and therefore has more potent transforming properties. Furthermore, the Ile31 variant of Aurora A binds poorly to E2 ubiquitin-conjugating enzyme, suggesting that the polymorphism may prevent degradation by ubiquitination, an important pathway for Aurora A activity regulation (6). Regarding the effects that Aurora A plays in chromosome instability and tumorigenesis, we hypothesized that the T91A polymorphism in Aurora A might act as a genetic modifier of individual susceptibility to certain cancers. On the basis of this hypothesis, we have recently shown in a molecular epidemiological study that the Aurora A Ile allele is significantly associated with the occurrence and advanced disease status of esophageal squamous cell carcinoma in a Chinese population (21). The present report describes a casecontrol study that aimed to examine the hypothesis in breast cancer. We genotyped 520 patients with primary breast carcinoma, 191 patients with benign breast disease (BBD) and 520 healthy controls and found that the Aurora A Phe31Ile polymorphism is associated with a risk of breast carcinoma.
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Materials and methods
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Study subjects
This hospital based casecontrol study consisted of 520 patients with primary breast carcinoma, 191 patients with BBD and 520 healthy controls. All subjects were unrelated ethnic Han Chinese women. Most of the breast carcinoma patients (n = 462) and normal controls (n = 509) were participants in a previously reported molecular epidemiological study of breast cancer (22). In the current study we added 58 more cases to extend the sample size of primary breast carcinoma to 520 to increase the statistical power. Briefly, the cases with primary breast carcinoma were consecutively recruited from January 1997 to January 2002 at the Cancer Hospital, Chinese Academy of Medical Sciences (Beijing). All eligible patients diagnosed at the hospital during the study period were recruited, with a response rate of 90%. Patients were from Beijing city and its surrounding regions and there were no age, stage or histology restrictions. The presence (M+) or absence (M) of detectable metastases was evaluated according to the UICC TumorNodeMetastasis (TNM) classification for breast carcinoma at diagnosis (23) on the basis of post-operative pathological examination of breast specimens. Patients with BBD were those who underwent surgical treatment for a solitary mammary lump subsequently found to be non-malignant by pathological examination. BBD includes adenosis (n = 97), fibroadenoma (n = 57), papilloma (n = 29) and other (three phyllode fibroadenomas, two ductal ectasias and three undefined BBDs). Healthy controls were from a nutritional survey conducted in the same region during the period of case collection (24). The control subjects were randomly selected from a database consisting of 2500 individuals based on a physical examination. The selection criteria included no history of cancer and frequency matching to breast carcinoma cases by age. At recruitment, informed consent was obtained from each subject and this study was approved by the Institutional Review Board of the Chinese Academy of Medical Sciences Cancer Institute.
Aurora A genotyping
Genomic DNA was isolated from the peripheral blood lymphocytes of the study subjects. Genotypes of Aurora A at the T91A (Phe31Ile) site were analyzed by PCRRFLP assay as described previously (21). The primers used for PCR were 5'-CTTTCATGAATGCCAGAAAGTT-3' and 3'-CTGGGAAGAATTTGAAGGACA-3'. Amplification was accomplished with a 25 µl reaction mixture containing 20 ng DNA, 0.2 µM each primer, 0.2 mM each dNTP, 1.5 mM MgCl2 and 1.0 U HotStarTaqTM DNA polymerase with 1x reaction buffer (Qiagen, Chatsworth, CA). The reaction was carried out under the following conditions: an initial melting step of 5 min at 95°C; 35 cycles of 30 s at 94°C, 30 s at 55°C and 30 s at 72°C; a final elongation step of 7 min at 72°C. The 165 bp PCR products were then digested with ApoI (New England BioLabs, Beverly, MA) and separated on a 2.5% agarose gel. The Phe allele had one ApoI restriction site that resulted in two bands (153 and 12 bp), whereas the Ile allele had two ApoI restriction sites and thus produced three bands (89, 64 and 12 bp). Genotypes of Aurora A revealed by PCRRFLP analysis were further confirmed by DNA sequencing. To ensure quality control, genotyping was performed without knowledge of the subjects' case/control status and a 15% random sample of cases and controls was genotyped twice by different persons; reproducibility was 100%.
Statistical analysis
2 tests were used to examine the differences in the distributions of genotypes between cases and controls. The associations between the Aurora A Phe31Ile polymorphism and risk of breast cancer or BBD were estimated by odds ratios (ORs) and their 95% confidence intervals (CIs), which were calculated by unconditional logistic regression. All ORs were adjusted for age where appropriate. All statistical analyses were performed using Statistical Analysis System software version 6.12 (SAS Institute, Cary, NC).
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Results
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The age distribution and clinical and histochemical features of study subjects are summarized in Table I. There was no significant difference between patients with breast carcinoma and controls in terms of age distributions (P = 0.908), suggesting that the frequency matching was adequate. However, although an effort was made to obtain a frequency match on age between patients with BBD and controls, younger subjects were presented in the group of BBD patients compared with the controls and the patients with breast carcinoma (P < 0.0001).
Allele frequencies and genotype distributions of the Aurora A Phe31Ile polymorphism in cases and controls are shown in Table II. In control subjects the frequencies of the Ile and Phe alleles were 62.1 and 37.9%, respectively, which differed significantly from those (69.8 and 30.2%) in breast carcinoma patients (P = 0.0002), but not those (64.7 and 35.3%) in patients with BBD (P = 0.379). The observed genotype frequencies in controls and cases with breast carcinoma or cases with BBD did not significantly deviate from those expected from the HardyWeinberg equilibrium (P = 0.520, 0.924 and 0.975, respectively). We observed a significant difference (P = 0.0003) in genotype distribution between cases with breast carcinoma (9.6% Phe/Phe, 41.1% Phe/Ile and 49.3% Ile/Ile) and controls (12.7% Phe/Phe, 50.4% Phe/Ile and 36.9% Ile/Ile). However, the frequencies of the three genotypes in BBD patients were not significantly different from those in controls (P = 0.350).
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Table II. Aurora A genotype and allele frequencies among controls, benign breast disease patients and breast carcinoma patients with different clinical and histochemical features
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Logistic regression analysis (Table III) showed that subjects homozygous for the Ile/Ile genotype had a 1.76-fold increased risk of developing breast carcinoma compared with those with the Phe/Phe genotype (95% CI 1.162.66). However, the heterozygous Phe/Ile genotype was not significantly associated with the risk of cancer (OR 1.08; 95% CI 0.711.62), suggesting a possible recessive effect of the polymorphism on breast carcinoma. Because of this observation, we further estimated the risk by combining Phe/Phe and Phe/Ile genotypes as the reference group and found that the OR of breast carcinoma for the Ile/Ile genotype was 1.66 (95% CI 1.292.12; P = 0.0001). However, no significant association was observed between the polymorphism and risk of overall BBD.
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Table III. The association of Aurora A genotypes with the risk of development of benign breast disease or breast carcinoma and disease status of breast carcinoma
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The risk of breast carcinoma and BBD associated with the Aurora A genotype was additionally examined with stratification by age. It was found that the increased risk of breast carcinoma associated with the Ile/Ile genotype compared with the Phe/Phe genotype was higher for the group aged <50 years at diagnosis (OR 2.15; 95% CI 1.173.96, P = 0.014) than for the group aged
50 years at diagnosis (OR 1.45; 95% CI 0.822.54, P = 0.202). Although the risk for BBD associated with the Ile/Ile genotype compared with the Phe/Phe genotype was also higher in women aged <50 years (OR 1.22; 95% CI 0.632.39; P = 0.557) than in women aged
50 years (OR 0.74; 95% CI 0.282.01; P = 0.558), they did not reach statistical significance. However, when the Phe/Phe and Phe/Ile genotypes were combined as the reference group, the Ile/Ile genotype was associated with a significantly increased risk of BBD among women aged <50 years (OR 1.61; 95% CI 1.062.45; P = 0.027) but not women aged
50 years (OR 0.68; 95% CI 0.351.33; P = 0.256).
Regarding the sex hormone receptor status of breast carcinoma, it appeared that the estrogen receptor (ER) patients were more likely than ER+ patients to carry the Ile/Ile genotype (59.2 versus 44.1%; P = 0.001) (Table II), with the OR being 2.56 (95% CI 1.245.26) compared with the Phe/Phe genotype (Table III). This association between the Ile/Ile genotype and ER status was independent of age of disease onset because ER status in this group of patients was not associated with age (mean ages ± SD were 50.2 ± 11.0 and 49.5 ± 11.0 for ER+ and ER patients, respectively; P = 0.305 for t-test). When ER status was combined with progesterone receptor (PR) status for analysis, the increased risk related to the Ile/Ile genotype was found to be more pronounced in the ER/PR subgroup (OR 2.07; 95% CI 0.934.62) compared with the ER+/PR+ subgroup.
We next examined the potential effect of the Aurora A genotype on tumor invasion and metastasis. No significant differences in Aurora A genotype frequencies between the M+ and M subgroups was observed (Table II), and the association between metastatic disease and the Ile/Ile genotype compared with the Phe/Phe genotype was not significant (OR 0.84; 95% CI 0.461.55; Table III). Likewise, no significant association between the polymorphism and disease status was found when the comparison was made with stage I patients compared with stage IIIV patients (OR 0.52; 95% CI 0.241.11; P = 0.090; Table III).
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Discussion
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This molecular epidemiological study examined whether the functional Phe31Ile (T91A) polymorphism in the mitosis-regulating gene Aurora A could have an impact on the risk of development and disease status of breast carcinoma. On the basis of analysis of 520 breast carcinoma patients and 520 frequency matched controls, we found that women carrying the Ile/Ile genotype had an increased risk of developing breast carcinoma. However, the heterozygous Phe/Ile genotype did not appear to be associated with the risk of cancer, suggesting a possible recessive effect of the polymorphism on breast carcinoma. We also found that patients carrying the lle/Ile genotype tended to lack expression of ER in their breast carcinomas. To the best of our knowledge, this is the first study to investigate the effect of Aurora A polymorphism on susceptibility to breast carcinoma.
Our results showing an association between risk of breast carcinoma and the polymorphism in Aurora A are biologically plausible for the following reasons. Firstly, there is broad evidence suggesting that Aurora A is an oncogene and its overexpression causes centrosome amplification, chromosome instability, malignant cell transformation and tumorigenesis (6,10,11,1517). Overexpression of Aurora A has been shown to occur in a high proportion of invasive breast carcinomas, pre-invasive carcinomas and even proliferative BBDs, indicating that Aurora A plays an important role in human mammary tumorigenesis (1315,17). Secondly, the Phe31Ile polymorphism in Aurora A has functional consequences (20). It has been shown that the Ile31 allele is amplified more commonly than the Phe31 allele in colon cancer patients and patients heterozygous for the Phe/Ile genotype had more aneuploidy than patients homozygous for the Phe/Phe genotype. Furthermore, Ile31 Aurora A has a greater capability than Phe31 Aurora A to induce cell growth in vitro and xenograft tumor formation in vivo in nude mice. On the other hand, compared with Phe31 Aurora A, Ile31 Aurora A shows poor binding to the E2 ubiquitin-conjugating enzyme UBE2N, suggesting that the Phe31Ile substitution may inhibit degradation of Ile31 Aurora A in the proper phase of the cell cycle and thus facilitate the oncogenic effect of Aurora A (20). Finally, the Phe31Ile polymorphism in Aurora A has been shown to be associated with increased risk of other types of human cancer (20,21). Taken together, these data strongly support our finding that functional Phe31Ile polymorphism in Aurora A is a genetic susceptibility factor for human mammary tumorigenesis.
In the present study we observed non-significant differences in the allele frequencies of the Aurora A polymorphism and OR associated with this polymorphism in overall BBD patients, but the number of subjects in the BBD group was relatively small and this might not have had the power to demonstrate a small effect. Thus, further studies with larger sample sizes are needed to clarify this issue. However, we found that risk of breast carcinoma associated with the Aurora A Ile/Ile genotype was more pronounced in younger subjects and the association between the Ile/Ile genotype and risk of developing BBD reached statistical significance in women aged <50 years (OR 1.61; 95% CI 1.062.45; P = 0.027). This observation is in line with the concept that genetic susceptibility is often associated with an early age of disease onset (2527). BBD is a risk factor for breast carcinoma and some kinds of BBD have been considered to be precancerous lesions (2831). Analysis of expression of Aurora A in breast carcinoma, BBD and normal breast tissues showed that Aurora A was overexpressed not only in the carcinoma specimens but also in BBD, including fibrocystic disease and fibroadenoma, whereas the protein was not detected in normal ductal and lobular cells (13). In the rat mammary carcinogenesis model overexpression of aurora A and centrosome amplification occurred at a very early, premalignant stage, prior to detectable lesions, after treatment with carcinogen (17). These data are parallel to our observations in the present study showing an association between the Ile/Ile genotype and risk for developing BBD in subjects aged <50 years. These findings indicate that Aurora A may play a role in the development of some BBDs and functional polymorphism in this mitosis-regulating gene may be a susceptibility factor involved in the early events leading to breast carcinoma.
Breast cancer is a sex steroid hormone-dependent tumor (19,32,33). Sex steroid hormones, especially estrogen, play an important role in the development of breast cancer. Early menarche, late menopause, benign breast disease and hormone replacement therapy have been shown to be associated with increased risk for breast cancer (34,35). However, the role of progesterone in breast cancer development is still arguable, but an early full-term pregnancy is regarded as a resistance factor (36). One hypothesis proposed to explain the parity effect is that hormonal stimulation by estrogen and progesterone induce a differential switch in a specific stem cell population that results in changes in the intracellular pathway governing proliferation and response to carcinogens (17). Several studies have shown that expression of Aurora A can be induced by estrogen in vitro and in vivo and overexpression of Aurora A is linked to breast carcinogenesis (17,18). In the present study we found that the risk of BBD and breast cancer associated with the Aurora A polymorphism was more pronounced in subjects aged <50 years than in subjects aged
50 years. This result might suggest a geneenvironment interaction between Aurora A and estrogen level, because 50 years old is the average age for menopause in Chinese women (37). Nevertheless, this issue needs further investigation.
Hormone receptor status is one of the most important prognostic factors for breast cancer (32). An increase in hormone receptor expression is associated with inhibition of cell proliferation and subsequently weakens tumorigenesis (33). Mastectomy patients with ER+ tumors show a lower incidence of recurrence and a longer disease-free interval, regardless of tumor size or lymph node status (38). However, the prognostic value of PR status is controversial. It has been suggested that PR status should be taken into account with ER status because patients with both ER+ and PR+ tumors usually have a better prognosis than patients with ER+ and PR tumors (39). However, patients with an ER tumor may have a worse prognosis if it is PR+ (40). In the present study, we found that patients carrying the Ile/Ile genotype tended to have ER carcinomas and this is the case even when PR status is considered. The significance and mechanism of this potential interaction between Aurora A genotype and ER status, a contributor to the risk of breast carcinoma, is not immediately evident. It might result from a selective growth advantage of cells that carry the Aurora A Ile31 allele and lack expression of ER. These results suggest that breast carcinomas with the Aurora A Ile/Ile genotype might be less likely to respond to endocrine therapy.
In a previous study on esophageal squamous cell carcinoma we found that the Aurora A Ile/Ile genotype was associated with a risk of both occurrence and advanced disease status of the cancer (21). In the present study, however, we did not observe any significant association between the polymorphism and clinical stage or metastasis of breast carcinoma. The reasons for the inconsistency in these results between esophageal squamous cell carcinoma and breast carcinoma are currently unclear. However, it might reflect the different effect of Aurora A on different types of cancer. It has been shown that overexpression of Aurora A is correlated with invasiveness and metastasis of certain cancers, such as bladder cancer (41), colon cancer (42) and esophageal cancer (Tong et al., unpublished data). For breast cancer, however, several studies have shown that overexpression of Aurora A is more relevant in tumor initiation than progression (14,15,43). These findings are in agreement with our results showing an association between the Aurora A polymorphism and risk of occurrence but not progression of breast carcinoma.
In conclusion, our study provides the first evidence that the Aurora A Ile/Ile genotype is associated with an increased risk for the occurrence but not progression of breast carcinoma. These molecular epidemiological findings further support the hypothesis that Aurora A is a candidate low penetrance tumor susceptibility gene in human.
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Received June 12, 2004;
revised July 15, 2004;
accepted July 18, 2004.