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TBX2 Is Preferentially Amplified in BRCA1- and BRCA2-related Breast Tumors¹

Departments of Laboratory Medicine and Pathology [C. S. S., C. A., C. L. S., M. J., L. W., V. L. C., R. B. J., F. J. C.], Epidemiology [T. A. S.], Biostatistics [D. S., J. S., Z. F.], Oncology [A. N., J. N. I., L. H.], and Biochemistry and Molecular Biology [R. B. J., F. J. C.], Mayo Clinic and Foundation, Rochester, Minnesota 55905

	ABSTRACT

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The chromosome 17q23 region is frequently amplified in breast tumors. Gain of the region is present in 50% of BRCA1-associated breast tumors and 87% of BRCA2-associated breast tumors. The amplification frequency of the RPS6KB1 and TBX2 oncogenes from this amplicon was compared in 27 BRCA1 and BRCA2 mutant breast tumors, 15 breast tumors from high-risk patients with no BRCA1 or BRCA2 mutations, and 62 matched sporadic breast tumor controls. TBX2 was determined to be preferentially amplified and overexpressed in BRCA1 and BRCA2 mutant tumors, whereas RPS6KB1 was not, suggesting a role for TBX2 amplification in the development of BRCA1- and BRCA2-associated breast tumors.

	Introduction

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Breast tumors in BRCA1 and BRCA2 carriers are pathologically and genetically distinct from sporadic tumors and appear to follow unique developmental pathways. In contrast to sporadic tumors, BRCA1 mutant breast tumors are of higher grade, predominantly estrogen receptor and progesterone receptor negative, and contain mutant p53 (1 , 2) . BRCA2-associated tumors tend to be of lower grade, have estrogen receptor and progesterone receptor levels comparable to those of sporadic tumors, and have fewer p53 mutations (1 , 2) . In addition, BRCA1- and BRCA2-associated breast tumors analyzed by CGH⁴ display twice as many chromosomal gains and losses as sporadic tumors (3) . Some specific genes displaying altered levels of amplification and expression in BRCA1- and BRCA2-associated breast tumors relative to sporadic tumors have been identified. The HER2/neu gene is amplified and overexpressed in 20% of sporadic tumors and BRCA2 tumors but is detected at significantly lower levels in BRCA1 tumors (1 , 4) . In contrast, the Myb oncogene is amplified in 29% of BRCA1 breast tumors but is not amplified in BRCA2 tumors and is amplified in only 2% of sporadic tumors (5) . Furthermore, cyclin D1 is amplified in 30% of sporadic breast tumors but is not amplified in tumors of BRCA1 or BRCA2 mutation carriers diagnosed before age 50 years (4 , 6) . Other chromosomal regions frequently amplified in BRCA1 and BRCA2 tumors have also been identified. For instance, the 17q22-q24 region is gained or amplified in 50% of BRCA1-associated breast tumors and 87% of BRCA2-associated breast tumors but in only 15% of sporadic tumors (3) . The selection for gain of this region suggests that a gene or genes localized to this region are important in the progression of hereditary breast tumors. We recently characterized the structure of a 4-Mb amplicon on chromosome 17q23 and have identified several independent peaks of amplification in breast cancer cell lines and in primary breast tumors (7) . The RPS6KB1 and TBX2 genes are located in the amplicon, are frequently amplified in human breast cancers, and are thought to contribute to tumor development (8, 9, 10, 11, 12) . RPS6KB1 is a ribosomal protein kinase that regulates protein synthesis and transition from G₁ to S phase of the cell cycle in response to mitogenic stimuli (13) . Amplification of the RPS6KB1 gene correlates with overexpression and poor survival in breast cancer patients (9) . The TBX2 gene is a T-box transcription factor that regulates gene expression during embryological development and facilitates senescence bypass in Bmi-/- mouse embryo fibroblasts when moderately overexpressed (11) . To determine whether these genes are preferentially amplified in hereditary breast tumors, we determined the copy number of RPS6KB1 and TBX2 in breast tumors from 27 carriers of BRCA1 and BRCA2 deleterious mutations, 15 patients who had a positive family history but were negative for deleterious mutations in BRCA1 and BRCA2 (NMD/UCV), and 62 sporadic controls using FISH.

	Materials and Methods

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Breast Tumors.
Twenty-seven BRCA1 and BRCA2 mutation carriers and 15 patients with a significant family history but with no deleterious BRCA1 or BRCA2 mutations were identified through the Familial Cancer Program high risk breast cancer clinic and a study of patients undergoing prophylactic mastectomy at the Mayo Clinic (14) . Because the 15 patients had NMD or had unique intronic variants or missense variants in BRCA1 or BRCA2 that are categorized as UCVs, this cohort will be referred to as NMD/UCV. Specimens from the NMD/UCV cohort were age-, stage-, and surgery date-matched by frequency with the BRCA1 and BRCA2 mutants. All mutations and sequence variants were identified either by conformation-sensitive gel electrophoresis followed by direct sequencing or by direct sequencing at Myriad Genetics Inc. (Salt Lake City, UT). Paraffin-embedded breast tumors from these patients were obtained from the Tissue Registry at the Mayo Clinic or from the hospital where the surgery was performed. Specimens from sporadic breast cancer controls were frequency-matched by age, stage, and surgery date with the BRCA1 and BRCA2 mutants and with the NMD/UCV cases. Note that perfect matching was not possible due to the limited availability of early-onset controls. A summary of all samples is provided in Table 1 . Deleterious mutations and UCVs of BRCA1 and BRCA2 are listed in Table 2 .

FISH Analysis.
Five-µm sections were cut from paraffin-embedded specimens, and tumor cells were identified after H&E staining. The TBX2 and RPS6KB1 BAC clones were dual-hybridized with the CEP17 (Vysis, Downer’s Grove, IL) centromere probe to sections from each specimen as described previously (15) . Sections were counterstained with 0.2 mM 4',6-diamidino-2-phenylindole in a Vectashield antifade solution (Vector Laboratories, Burlingame, CA), and FISH signals were enumerated using a Zeiss Axioplan microscope equipped with a triple-pass filter. Two readers scored at least 200 nuclei from each sample for the 17q23 probes and centromere probe. The copy number ratio was calculated by dividing the number of 17q23 probe signals by the number of centromere signals. Low-level amplification is defined as a ratio between 1.5 and <2.0. Amplification is defined as a ratio 2.0 and includes moderate (ratio 2.0 and <3.0) and high level (ratio 3.0) amplification. By choosing a minimum ratio of 1.5, our frequencies of amplification closely match those from a previous CGH study of BRCA1- and BRCA2-associated tumors and sporadic tumors (3) . Likewise, with a ratio of 2.0, the frequencies of amplification match our previously reported Southern blot data from sporadic tumors (7) .

Statistical Analysis.
Statistical differences in the frequency of amplification between the BRCA1 and BRCA2 mutant tumors, the NMD/UCV tumors, and the controls were tested for statistical significance by Fisher’s exact test.

RNA in Situ Hybridization.
A 427-bp fragment of the TBX2 coding sequence was amplified by PCR with primers F-AGCTGAGGAGAAGTCGTGCG and R-GTGCAGGAAGAGCGGCTG and cloned into the pCRII-TOPO vector (Invitrogen). Sense and antisense digoxigenin-labeled RNA probes were generated from the linearized plasmid using the DIG RNA Labeling Kit (Roche Molecular Biochemicals). In situ hybridization of 5-µm sections from paraffin blocks of breast tumors was performed according to the manufacturer.

	Results

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TBX2 Amplification in Breast Tumors by FISH.
To determine whether the TBX2 gene is preferentially amplified in BRCA1- and BRCA2-associated tumors, we performed FISH on tumors from BRCA1 and BRCA2 mutation carriers, NMD/UCVs, and sporadic controls with the TBX2 BAC clone hRPK.332_H_18. Amplification (hRPK.332_H_18:CEP17 ratio 1.5) was detected in 19 of 27 BRCA1 and BRCA2 tumors but in only 8 of 37 matched sporadic controls (P = 0.0001), as shown in Table 3 . Similarly, amplification (ratio 2.0) was found in 8 of 27 BRCA1 and BRCA2 tumors but in only 3 of 37 sporadic controls (P = 0.04). In contrast, TBX2 amplification (ratio 1.5) was detected in only 3 of 15 NMD/UCV tumors and 5 of 25 matched controls (P = 1.0), whereas ratios 2.0 were detected in 1 of 15 NMD/UCVs and 3 of 25 sporadic controls (P = 1.0). Thus, TBX2 is selected preferentially for amplification in tumors from BRCA1 and BRCA2 mutation carriers when compared with tumors from patients with a family history but no BRCA1 or BRCA2 mutations or with sporadic tumors. Examples of amplification of TBX2 in tumors are shown in Fig. 1, A and B .

View larger version (126K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Amplification of TBX2 and RPS6KB1 in breast tumor cells. TBX2 probe and RPS6KB1 probe signals are shown in red, and chromosome 17 centromere probe (CEP17) signals are shown in green. A, FISH demonstrating amplification (ratio 2.0) of TBX2 in DCIS. B, FISH of DCIS with low-level amplification (ratio = 1.5–2.0) of TBX2. C, FISH of DCIS showing amplification (ratio 2.0) of RPS6KB1. D, FISH demonstrating low-level amplification (ratio = 1.5–2.0) of RPS6KB1 in DCIS.

A hallmark of BRCA1 and BRCA2 tumors is early age of onset. To determine whether TBX2 is preferentially amplified in patients with earlier age of onset, we analyzed the subsets of <42 years and 42 years to reflect the average age of onset for BRCA1 and BRCA2 tumors. TBX2 was amplified (ratio 2.0) in 2 of 12 BRCA1 and BRCA2 mutation carriers <42 years and in 6 of 15 BRCA1 and BRCA2 mutation carriers 42 years (P = 0.2). This suggests that TBX2 is not preferentially amplified in tumors with an earlier age of onset.

RPS6KB1 Amplification in Breast Tumors by FISH.
To determine whether other parts of the amplicon and specifically the RPS6KB1 gene are also selected preferentially for amplification in BRCA1 and BRCA2 mutant tumors, we evaluated the frequency of amplification of hRPC.1073_F_15 containing the RPS6KB1 gene in the same series of tumors. RPS6KB1 was amplified (ratio 1.5) in 11 of 27 BRCA1-and BRCA2-associated tumors and 15 of 37 matched sporadic controls (P = 1.0), as shown in Table 3 . Amplification (ratio 2.0) was observed in 3 of 27 BRCA1 and BRCA2 tumors and 4 of 37 sporadic controls (P = 1.0). This suggests that RPS6KB1 is not preferentially amplified in BRCA1- and BRCA2-associated tumors. Similarly, 1 of 15 NMD/UCVs and 5 of 25 sporadic tumors had RPS6KB1 amplification (ratio 1.5; P = 0.38). Amplification (ratio 2.0) was not detected in the NMD/UCVs but was detected in 3 of 25 matched sporadic controls (P = 0.28). These data suggest that the RPS6KB1 gene is also not preferentially amplified in the NMD/UCV breast tumors. We also examined the amplification by tumor stage, patient age at onset, and tumor type and found no trends toward significant differences between the amplification in BRCA1 and BRCA2 tumors and the matched sporadic controls. Examples of tumors with RPS6KB1 amplification are shown in Fig. 1, C and D .

TBX2 and RPS6KB1 Amplification in BRCA1 Tumors Compared with BRCA2 Tumors.
Because TBX2 is apparently preferentially amplified in the tumors with deleterious mutations in BRCA1 and BRCA2, we evaluated whether TBX2 amplification was more frequent in BRCA1- or in BRCA2-associated tumors. TBX2 amplification (ratio 1.5) was seen in 8 of 13 BRCA1 tumors and 11 of 13 BRCA2 tumors (P = 0.38). Similarly, amplification (ratio 2.0) was seen in 6 of 13 BRCA1 tumors compared with 2 of 13 BRCA2 tumors (P = 0.20), suggesting that BRCA1 and BRCA2 tumors are equally likely to display amplification of this region, although the small sample size limits the ability to detect significant differences. Likewise, no difference in amplification frequency of RPS6KB1 in BRCA1 and BRCA2 tumors was detected.

TBX2 and RPS6KB1 Coamplification in BRCA1 and BRCA2 Tumors and Controls.
To determine whether selection for specific regions of the amplicon occurs in sporadic and BRCA1 and BRCA2 tumors with amplification, we differentiated between tumors with independent amplification and coamplification of the probes. Of the tumors with amplification (ratio 1.5), TBX2 was amplified independently of RPS6KB1 in 9 of the 20 BRCA1 and BRCA2 tumors and 1 of 16 sporadic controls (P = 0.02). In contrast, RPS6KB1 was amplified independently of TBX2 in only 1 of 20 BRCA1 and BRCA2 tumors with amplification, whereas 8 of 16 sporadic controls had independent amplification of RPS6KB1 (P = 0.005). Coamplification of both probes was seen in 10 of 20 BRCA1 and BRCA2 tumors and 7 of 16 matched sporadic controls (P = 0.75). These data suggest that TBX2 amplification is selected for in BRCA1 and BRCA2 tumors, whereas RPS6KB1 amplification is selected for in sporadic tumors.

TBX2 Overexpression in Tumors with TBX2 Amplification.
To verify that TBX2 was overexpressed in tumors with TBX2 amplification, we performed RNA in situ hybridization of sections from paraffin blocks that were previously used for FISH analysis. The 427-bp TBX2 riboprobe was chosen from a region of minimal homology between T-box gene family members to ensure that RNA in situ signals represented TBX2 expression alone. BRCA1 and BRCA2 mutant tumors in which TBX2 was amplified showed high levels of TBX2 expression, as shown in Fig. 2, A and B . Specifically, epithelial tumor cells displayed significant expression, as did infiltrating T cells, whereas stromal and fat tissue showed little or no expression. Similarly, TBX2 was highly expressed in epithelial tumor cells from sporadic breast tumors in which TBX2 was amplified (Fig. 2C) . However, the stroma and the normal ductal epithelial cells in this tumor section showed little expression of TBX2 (Fig. 2C) . In contrast, BRCA1 and BRCA2 mutant tumors and sporadic tumors that did not have amplification of the TBX2 gene showed no significant expression of TBX2 (data not shown).

View larger version (79K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Overexpression of TBX2 in breast tumors with TBX2 amplification. RNA in situ hybridization with TBX2 antisense and sense probes, respectively, in a BRCA2 mutant breast tumor (A and D), BRCA1 mutant breast tumor (B and E), and sporadic breast tumor (C and F) with TBX2 amplification.

	Discussion

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Previous CGH analysis of breast tumors from BRCA1 and BRCA2 mutation carriers detected gain of the 17q22-q24 region in 50% of BRCA1 tumors, 87% of BRCA2 tumors, and 15% of sporadic controls (3) . Here we report that the TBX2 gene is amplified in 62% of BRCA1 tumors, 85% of BRCA2 tumors, and 22% of sporadic controls, whereas RPS6KB1 is amplified in only 11% of BRCA1 and BRCA2 tumors and sporadic controls. This suggests that TBX2 may be the target gene driving amplification of the 17q22-q23 region in BRCA1- and BRCA2-associated tumors, whereas RPS6KB1 is not. However, given the complexity of the amplicon and the presence of several candidate genes in other amplification peaks, it is possible that other genes in the region may also be targets of amplification and may contribute to the development of breast tumors in BRCA1 and BRCA2 mutation carriers, NMD/UCV cases, or sporadic cases.

TBX2 is a member of a family of phylogenetically conserved DNA-binding proteins known to regulate gene expression during development. Low to moderate overexpression of the TBX2 protein represses the Cdkn2a (p19^ARF) promoter and disables the Cdkn2a checkpoint, leading to bypass of senescence and immortalization of Bmi-/- primary mouse embryo fibroblasts (11) . Amplification of TBX2 appears to be selected for at high frequency in tumors from BRCA1 and BRCA2 mutation carriers and may assist early-stage tumor cells in bypassing senescence. This hypothesis is supported by the observation that TBX2 is amplified as frequently in DCIS specimens as in invasive tumors. Additional studies of TBX2 amplification in premalignant breast lesions may be helpful in determining whether this is an initiating event in the development of these tumors. However, TBX2 amplification and overexpression are not required for tumor development in all BRCA1 and BRCA2 mutation carriers because 30% of the BRCA1 and BRCA2 tumors studied did not have amplification. Thus, amplification and associated overexpression of TBX2 may be an early contributing event in initiation and development of a select group of BRCA1- and BRCA2-associated tumors.

In an effort to determine whether the preferential amplification of TBX2 is associated with a family history of breast cancer or is specific for BRCA1 and BRCA2 mutation carriers, we analyzed amplification in a group of patients with significant family history but with no deleterious BRCA1 or BRCA2 mutations. These NMD/UCV samples contain unique intronic variants or missense variants categorized as UCVs of BRCA1 and BRCA2. Unlike truncating mutations, which remove downstream sequence encoding protein domains and the nuclear localization signal, these UCVs may disrupt a single domain, leaving the rest of the protein intact, or, more likely, may have no effect on the protein. If UCVs of BRCA1 and BRCA2 have no role in tumor development, the presence of a strong family history of breast cancer in these patients suggests that other predisposition genes may be involved. In this study, we found no significant difference in the frequency of amplification of either TBX2 or RPS6KB1 between the NMD/UCV tumors and matched controls, but we did detect preferential amplification of TBX2 in BRCA1 and BRCA2 tumors compared with the NMD/UCV tumors. These data suggest that amplification of TBX2 is unique to the BRCA1- and BRCA2-related breast cancers and that the NMD/UCV tumors follow a different developmental pathway than the BRCA1 and BRCA2 tumors.

In conclusion, we have found that the TBX2 gene is more frequently amplified in breast tumors from BRCA1 and BRCA2 mutation carriers than in NMD/UCVs and sporadic tumor controls. These findings suggest that the TBX2 gene is specifically selected for amplification and overexpression in BRCA1 and BRCA2 tumors and may therefore be a useful predictive/prognostic marker in familial breast tumors. On the other hand, RPS6KB1 amplification and overexpression are more commonly found in sporadic tumors. This apparent selection in sporadic tumors, in combination with the recent finding that amplification and overexpression of RPS6KB1 correlate with poor survival in breast cancer patients (9) , indicates that RPS6KB1 may be a useful and specific predictive/prognostic marker for patients with sporadic tumors. The reasons for these differences in amplification within the 17q23 amplicon are not clear but suggest the existence of very specific tumor developmental pathways.

	ACKNOWLEDGMENTS

 
We thank Kari Anderl and Mark Law for assistance with FISH analysis and Christene Hettinga for assistance with the preparation of the manuscript.

	FOOTNOTES

 
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.

¹ Supported in part by a grant from the Breast Cancer Research Foundation (to J. N. I. and F. J. C.); Department of Defense Grant DAMD17-1-99-9282 (to F. J. C.); NIH Grants CA82267 (to T. A. S., D. S., L. H., and F. J. C.), CA80181 (to T. A. S., D. S., L. H., R. B. J., and F. J. C.), and CA87898 (to F. J. C.), and NIH Training Grant CA75926 (to C. S. S.).

² C. S. S. and C. A. contributed equally to this work.

³ To whom requests for reprints should be addressed, at Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street, S.W., Rochester, MN 55905. Phone: (507) 266-0878; Fax: (507) 266-0824; E-mail: couch.fergus{at}mayo.edu

⁴ The abbreviations used are: CGH, comparative genomic hybridization; FISH, fluorescence in situ hybridization; BAC, bacterial artificial chromosome; DCIS, ductal carcinoma in situ; IDC, infiltrating ductal carcinoma; NMD, no mutations detected; UCV, unclassified variant.

Received 1/ 9/02. Accepted 5/10/02.

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