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Epidemiology and Prevention |
1 Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine and 2 Department of Preventive Medicine, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois; 3 Human Genetics Program, Department of Pediatrics, New York University Medical Center; 4 Department of Medicine and 5 Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center; 6 Department of Epidemiology, Mailman School of Public Health and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
Requests for reprints: Boris Pasche, Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 676 North St. Clair Street, Suite 880, Chicago, IL 60611. Phone: 312-695-0320; Fax: 312-695-0318; E-mail: b-pasche{at}northwestern.edu.
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Introduction |
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Mouse models have allowed demonstration that increased TGF-ß signaling is associated with decreased cancer incidence. This association has been found with both transgenic mice expressing higher TGFB1 levels (6, 7) and mice with increased TGF-ß signaling because of constitutively active TGFBR1 receptor (8). On the other hand, the same sets of experiments have documented that the growth of tumors is fueled by increased TGFB1 levels and by increased TGF-ß signaling. Hence, these in vivo experiments indicate that higher TGFB1 levels serve as a surrogate of increased TGF-ß signaling and lower TGFB1 levels a surrogate for decreased TGF-ß signaling. This dichotomy of function for TGF-ß serves as the basis of the hypothesis to be tested in this study.
Five polymorphisms have been identified in the TGFB1 gene to date (9). Two are in the promoter region (C-509T and G-800A), one within the signal sequence (Leu10Pro), one within exon 1 (Arg25Pro), and one within exon 5 (Thr263Ile). The C-509T single nucleotide polymorphism (SNP) is not contained within a known consensus sequence for a promoter regulatory element and does not affect breast cancer risk (10), but one report indicates that it may modify TGFB1 expression (11). There is evidence that the Arg25Pro polymorphism modifies TGFB1 circulating levels (12–14), but it has not been associated with breast cancer risk thus far. The Leu10Pro polymorphism has been extensively studied in relation to breast cancer risk. The CC (TGFB1*CC) genotype (Leu10Pro polymorphism) was found by one group of investigators to be associated with a 64% decreased breast cancer risk in a cohort study of 3,075 White American women over age 65 years at recruitment (15). In contrast, in a pooled analysis of three European case-control studies that included 3,987 cases and 3,867 controls, the CC genotype was associated with a 21% increased risk of breast cancer. In the same study, the investigators found that the C-509T and the T29C SNPs but not the G-800A were in strong linkage disequilibrium and that they were both significantly associated with increased incidence of invasive breast cancer in a recessive manner. In a hospital-based study of 232 cases and 172 controls conducted in Japan, there was no significant overall association between the CC genotype and breast cancer. However, the CC genotype was associated with a 65% reduced risk of breast cancer in comparison with the TT genotype among premenopausal women [odds ratio (OR), 0.45; 95% confidence interval (95% CI), 0.20-0.98; ref. 16]. A German study of 500 cases and 500 controls did not find any statistically significant association between either TGFB1*CC and TGFB1*CT genotypes and breast cancer (17). Most recently, a large multiethnic case-control study of 1,123 breast cancer cases and 2,314 controls from Los Angeles and Hawaii also did not find any association between the TGFB1*CC genotype and breast cancer risk (18).
Of major interest in this regard is the recent report that patients with a diagnosis of breast cancer that carry the TGFB1 C variant that results in higher circulating TGFB1 levels have a significantly decreased survival compared with noncarriers (19). This polymorphism is represented by a SNP at position 29, which results in the substitution of leucine to proline at the 10th amino acid position (Leu10Pro). The leucine-to-proline substitution results in significantly higher TGFB1 in vivo levels among TGFB1*CC carriers (20–22). The Leu10Pro signal peptide substitution is well characterized for its effects on the regulation of TGFB1 secretion. Transfection of HeLa cells with constructs encoding either proline or leucine forms of TGFB1 and driven by the cytomegalovirus promoter show that the signal peptide with proline (C variant) at residue 10 causes a 2.8-fold increase in secretion compared with the leucine (T variant) form (10). Hence, there is both in vitro and in vivo evidence to support the conclusion that the T29C SNP is the most relevant SNP that modifies the amount of secreted and circulating TGFB1 and affects overall TGF-ß signaling. The function of the other TGFB1 polymorphisms and their relevance to breast cancer risk remains to be further characterized.
We have previously identified TGFBR1*6A, a common variant of TGFBR1. TGFBR1*6A has a deletion of three GCG triplets coding for alanine within a nine alanine (9A) repeat sequence of TGFBR1 (TGFBR1*9A) exon 1, resulting in a six alanine (TGFBR1*6A) repeat sequence (23). The 9-bp deletion that differentiates TGFBR1*6A from TGFBR1 is located within the predicted signal sequence cleavage region. Two separate groups of investigators have shown that TGFBR1*6A mediates TGF-ß growth inhibitory signals significantly less effectively than TGFBR1 (24, 25). TGFBR1*6A is a candidate tumor susceptibility allele that is associated with an increased incidence of various types of cancer (26, 27). The first report of an association between breast cancer and TGFBR1*6A was a case-control study of 355 women with breast cancer and 248 controls by Baxter et al. (26). In that study, TGFBR1*6A was associated with a 60% increased risk of breast cancer. These results are further supported by our recent meta-analysis of eight case-control studies that included 1,420 breast cancer cases and 1,823 controls, which showed that TGFBR1*6A predisposes to the development of breast cancer (OR, 1.38; 95% CI, 1.14-1.67; ref. 28).
Thus, differences in TGF-ß signaling, whether mediated by ligand or receptor variants, have been associated with risk for breast cancer. Various genotypic combinations may theoretically have either opposite or synergistic effects on breast cancer risk.
It is known that TGFB1 and TGFBR1 map to different chromosomes, 19q13.1 and 9q22, respectively. Thus, they are independently inherited. This has led us to hypothesize that the TGFB1 T29C and the TGFBR1*6A variants have a functional interaction with respect to breast cancer risk. Furthermore, based on genotyping of these two variants, we hypothesized that individuals with the combination of these two variants resulting in the highest predicted levels of TGF-ß signaling have the lowest breast cancer risk and conversely those with the lowest levels of TGF-ß signaling the highest breast cancer risk.
To test the hypothesis that a combined assessment of TGF-ß pathway signaling variants may predict breast cancer risk more accurately than each variant alone, we genotyped 660 women with a diagnosis of breast cancer and 841 healthy female controls for the two most common and biologically relevant variants of the TGF-ß signaling pathway, TGFB1 T29C and TGFBR1*6A.
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DNA isolation. DNA from whole blood lymphocytes was extracted using the QIAamp DNA blood mini kit and stored at –20°C until use for genotyping.
TGFB1 genotyping. The first variant is a TGFB1 T-to-C point mutation at position 10 resulting in a leucine-to-proline substitution. Part of the TGFB1 gene was amplified by PCR according to the following conditions: initial denaturation at 95°C for 10 minutes followed by 35 cycles at 93°C for 20 seconds, 65°C for 30 seconds, and 72°C for 30 seconds. The last extension step was prolonged to 3 minutes. The reactions were carried out in a total volume of 50 µL containing 100 to 300 ng genomic DNA, 1x standard PCR buffer without MgCl2, 1.5 mmol/l MgCl2, 6% DMSO, 25 pmol of primers, 200 µmol/L of each deoxynucleotide triphosphate, and 1 unit Taq DNA polymerase. The primers used were 5'-TGCCGCCCTCCGGGCTGCGGCTGCGGC-3' and 5'-TCTTGCAGGTGGATAGTCCCGCGGTCGG-3'. The PCR product is 102 bp long. The PCR product was cleaved with HaeIII overnight. The resulting fragments from the HaeIII digestion were separated on a 12% gel in 0.5x Tris-borate EDTA buffer and visualized with ethidium bromide. Digestion by restriction enzyme HaeIII generates polymorphic fragments of 69, 43, and 26 bp, respectively, and a 33-bp nonpolymorphic fragment. The various genotypes were confirmed by direct sequencing.
TGFBR1 genotyping. The second variant is a 9-bp deletion within a stretch of nine GCG repeats coding for alanine (29). PCR amplification was done using intronic primers flanking TGFBR1 exon 1: 5'-GAGGCGAGGTTTGCTGGGGTGAGGCA-3' and 5'-CATGTTTGAGAAAGAGCAGGAGCGAG-3'. Genotyping was done as described previously (24). Briefly, PCR amplification was done according to the following conditions: initial denaturation at 95°C for 1 minute followed by 35 cycles at 94°C for 30 seconds and 68°C for 3 minutes. The last extension step was prolonged to 3 minutes. The reactions were carried out in a total volume of 25 µL containing 100 to 300 ng genomic DNA using the Advantage GC-genomic kit (Clontech, Palo Alto, CA). For single-strand conformational polymorphism analysis, PCR product (5 µL) was mixed with 10 µL formamide dye. The solution was heated at 95°C for 5 minutes, placed on ice water for 1 minute, and then loaded on the single-strand conformational polymorphism gel. The single-strand DNA fragments were resolved on a 20% Tris-borate EDTA acrylamide gel. Results for the different polymorphisms were confirmed by direct sequencing.
High, intermediate, and low signalers. Previous studies have shown that TGFBR1*6A is a hypomorphic form of TGFBR1 (24, 25). Hence, all TGFBR1*6A carriers were classified as low signalers, with the exception of individuals carrying both TGFBR1*6A and the TGFB1*CC genotype that were classified as intermediate signalers (Fig. 1). The TGFB1 T-to-C substitution has been shown to result in higher TGFB1 secretion (10). TGFB1*CC carriers have significantly higher TGFB1 circulating levels than carriers of the TGFB1*CT and TGFB1*TT genotypes (30). Individuals carrying the TGFB1*CC genotype and with two copies of the wild-type TGFBR1 (i.e., a TGFBR1 that transduces TGF-ß signals more efficiently than TGFBR1*6A) were classified as high signalers. Individuals with other genotypic combinations were classified as intermediate signalers (Fig. 1).
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Statistical analysis. Distributions of TGFBR1 genotypes, TGFB1 genotypes, age, and ethnicity were compared between cases and controls using 
2 tests. To examine the effect of TGFBR1 and TGFB1 genotypes adjusting for covariates, ORs for breast cancer were estimated using unconditional logistic regression models. Both crude and adjusted ORs for breast cancer were estimated comparing carriers of TGFBR1*6A and C allele versus noncarriers for TGFBR1 and TGFB1, respectively, under dominant, additive, and recessive genetic susceptibility models. Age and ethnicity were controlled for in all analyses. Crude and adjusted ORs are similar, and we reported adjusted ORs. Additionally, adjusted ORs were estimated comparing joint states of the TGFBR1 and TGFB1 genotypes by a priori categorizing subjects as high, intermediate, and low signalers based on the known functional status of the variant alleles (refs. 10, 24, 25; Fig. 1). Trend statistics were conducted to assess whether risk of breast cancer increases according to this a priori categorization. A small P of the trend test indicates that breast cancer risk is related to the scoring based on TGFBR1 and TGFB1 genotypes. Whether the effects of TGFBR1 and TGFB1 on breast cancer differ by age was evaluated by stratified analysis and tests for multiplicative interaction. A small P indicates that interaction of age and gene is statistically significant on the multiplicative scale.
Sensitivity analysis was conducted to evaluate the effect of the fact that the exact age of a large number of controls is not known. In the subgroup of those with known exact age, ORs were estimated with or without adjusting age as a continuous variable. In the overall study population, ORs were estimated not only with or without adjusting age as a categorical variable but also under different scenarios by assigning controls with unknown exact age with values of lowest and highest extremes (i.e., all 20 or all 40). Analysis was also conducted for extreme scenarios where all carrier controls were assumed to be 40 years old and all noncarrier controls 20 years old and vice versa. An additional analysis was done to identify possible differences in TGFBR1 and TGFB1 allelic frequencies among the various age groups of controls for whom exact age was known. Because a subset of cases had data on tumor prognostic characteristics available, we conducted polytomous logistic regression to calculate ORs by comparing each of the case groups with the total controls with respect to TGFB1 and TGFBR1 status.
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50 years (OR, 2.05; 95% CI, 1.01-4.16; Table 3).
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50 years (OR, 1.18; 95% CI, 0.75-1.84; Table 3). To assess the possibility that the effect of TGFBR1*6A on breast cancer risk is nullified by the TGFB1 T29C variant, we restricted the analysis to TGFB1*CC and TGFB1*TC carriers. Breast cancer risk remained significantly higher for TGFBR1*6A carriers (OR, 1.58; 95% CI, 1.04-2.39). TGFB1*CC and breast cancer risk. About 18.1% of cases and 21.6% of controls carried the TGFB1*CC genotype (Table 1). There was a trend toward decreased breast cancer risk for carriers of the TGFB1*CC genotype, but it did not reach formal significance (OR, 0.89; 95% CI, 0.63-1.21). The results were similar under either an additive or a recessive model. Adjustment for age and ethnic status did not change the results (Table 2). The observed trend toward decreased breast cancer for TGFBR1*CC carriers was similar for women above or below age 50 years (Table 3).
Estrogen receptor, progesterone receptor, and stage at diagnosis. Information on ER and PR status and stage at diagnosis was available for 152 patients. There was no association between TGFBR1*6A and ER and PR status and stage at diagnosis (Table 4). On the contrary, both TGFB1*CT and TGFB1*CC were more likely to have advanced stage as assessed by the presence of lymph node metastasis and stage III or IV at diagnosis (Table 4). Patients carrying the TGFB1*CC genotype were more likely to have ER-negative and PR-negative tumors (Table 4).
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Discussion |
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TGFB1 exerts pleiotropic effects in the oncogenesis of breast cancer in a contextual manner (i.e., it suppresses tumorigenesis at an early stage by direct inhibition of angiogenesis and tumor cell growth). However, overproduction of TGFB1 by advanced tumors may accelerate disease progression through indirect stimulation of angiogenesis and immune suppression (33). Evidence also exists that TGF-ß signaling contributes to the metastasis in breast cancer (34, 35) and that TGF-ß signaling blockade inhibits mammary tumor cell viability, migration, and metastasis (36). The contribution of TGF-ß to the malignant phenotype of breast cancer cells is particularly prominent in cell lines that retain the TGF-ß signal transduction system but have lost TGF-ß-induced growth inhibition. Such is the case in breast cancer cells with a hyperactive Ras pathway (35, 37, 38).
Both stromal and epithelial cells from TGFB1*CC are likely surrounded by more TGFB1 than cells from TGFB1*TT individuals given the fact that the TGFB1 Leu10Pro (T29C) results in higher in vitro TGFB1 secretion and the TGFB1*CC genotype is associated with higher TGFB1 serum levels (10, 39). In our report, the higher frequency of lymph node metastases and the more advanced stage at diagnosis in carriers of the TGFB1*CC and TGFB1*CT genotypes are in agreement with these laboratory findings and with the recent report of a significantly reduced 5-year survival among patients with breast cancer that carry the TGFB1*CC and TGFB1*CT genotypes (40).
Taken together, these results are additional evidence that increased TGF-ß signaling due to a naturally occurring variant is associated with a more aggressive tumor behavior. If confirmed in larger studies, TGFB1 genotype may become a new prognostic marker for women diagnosed with breast cancer and the TGF-ß signaling pathway may become a molecular target for therapeutic interventions. The additional finding of an increased proportion of ER-negative and PR-negative tumors among carriers of the TGFB1*CC genotype points to the fact that increased TGF-ß signaling results in more aggressive tumor behavior in the absence of ER and PR overexpression.
This may explain the conflicting results of the Ziv et al. (10), Dunning et al. (15), and Le Marchand et al. (18) studies. Among premenopausal women, the proportion of tumors overexpressing ER and PR is lower than among postmenopausal women. Hence, the growth of ER-negative and PR-negative tumors from premenopausal women may benefit from increased TGFB1 levels, whereas growth of the predominantly ER-positive and PR-positive tumors from postmenopausal women may not be similarly affected by higher TGFB1 levels. Subjects enrolled in the Ziv et al. study were ages 65 years with a mean age of 70 years. Subjects in the Le Marchand et al. study were predominantly postmenopausal with a mean age of 63 years. Conversely, the Dunning et al. study reported a combined analysis of three case-control studies, including breast cancer cases with a mean age of 50 years, and showed that TGFB1*CC and TGFB1*CT carriers had a slight but significant increased risk of invasive breast cancer. Although not significant, our results show a trend similar to that of the former study. The mean age of our cases was 5 years higher than the Dunning study, 15 and 10 years lower than the Ziv et al. and Le Marchand et al. studies, respectively. Given that the mean age at menopause in the general population is 50 years, the proportion of postmenopausal women in our population is likely higher than in the Dunning et al. study and may explain the nonsignificant trend toward a TGFB1*CC protective effect. The findings that differences in TGF-ß signaling effects are more pronounced among postmenopausal women further support this explanation. However, another plausible explanation for these conflicting results is the functional interaction between TGFBR1*6A and the TGFB1 T29C polymorphism shown in this report.
Our study has several limitations. Due to destruction of personal identifiers, we only had exact age information in a subset of our controls. For the remainder of controls, only the age range was available. Furthermore, cases and controls were not matched for variables known to be associated with breast cancer. However, we did analyses controlling for age. We also conducted sensitivity analyses using hypothetical models to show that the effect of the lack of detailed age information in a portion of our samples was negligible. It is possible that age differences in cases and controls affected the allele frequencies observed. Nonetheless, this would be expected to create a bias toward the null hypothesis because it would overestimate the deleterious allele frequency in controls given that a fraction of younger women who would have developed breast cancer were not removed from the control group. Thus, all the younger mean age of controls could have resulted in a bias toward the null hypothesis, resulting in a weaker association. In addition, an additional limitation of our study is the lack of analysis of other TGFB1 polymorphisms, some of which may modify TGFB1 circulating levels (41).
Another potential drawback is the lack of complete pathologic information in our cases. Due to the destruction of the personal identifiers, we could not retrospectively collect data on ER/PR and the lymph node status in a subset of patients. However, taking into account the limited number of cases with complete histopathologic information, our significant results in the advanced stage and ER-negative population merit further investigation in a large prospective study.
The results presented here reflect a nonselected population of patients with breast cancer. TGFBR1*6A carriers (15.7% of cases and 11.3% of controls) and high TGF-ß signalers (15.1% of cases and 21.4% of controls) make up >30% of the population of both cases and controls. This is evidence that variants of the TGF-ß signaling pathway are likely to modify breast cancer risk in a large subset of the population. Studies are in progress to determine the contribution of the TGF-ß signaling pathway variants to familial and sporadic breast cancer.
The combined analysis of high versus low signalers is the first indication in humans that altered TGF-ß signaling modifies breast cancer risk. It identifies high signalers as a subgroup of individuals with increased TGF-ß signaling and decreased breast cancer risk, although, taken separately, the proportion of TGFB1*CC and TGFBR1/TGFBR1 carriers was similar among cases and controls. It also shows that combination of naturally occurring TGF-ß signaling pathway variants probably result in functional differences large enough in vivo to modify breast cancer risk, similar to what has been shown recently in transgenic mouse models (8). These results warrant validation in well-designed case-control studies to explore further the role of TGF-ß signaling pathway variants with respect to breast cancer risk and outcome.
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Acknowledgments |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8/17/04. Revised 12/15/04. Accepted 2/ 3/05.
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References |
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C polymorphism in the transforming growth factor ß1 gene and breast cancer among elderly white women: The study of osteoporotic fractures. JAMA 2001;285:2859–63. C polymorphism of the transforming growth factor-ß1 gene with genetic susceptibility to myocardial infarction in Japanese. Circulation 2000;101:2783–7. C polymorphism of the transforming growth factor-ß1 gene with genetic susceptibility to myocardial infarction in Japanese. Circulation 2000;101:2783–7.
C polymorphism of the transforming growth factor-ß1 gene with genetic susceptibility to myocardial infarction in Japanese. Circulation 2000;101:2783–7.
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