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[Cancer Research 60, 2756-2759, June 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Amplification in Human Breast Cancer of a Gene Encoding a c-myc mRNA-binding Protein1

Glenn A. Doyle, Jeanne M. Bourdeau-Heller, Stephanie Coulthard, Lorraine F. Meisner and Jeffrey Ross2

McArdle Laboratory for Cancer Research, Department of Oncology [G. A. D., J. R.], and Wisconsin State Laboratory of Hygiene, Cytogenetics Section [J. M. B-H., S. C., L. F. M.], University of Wisconsin-Madison, Madison, Wisconsin 53706


   ABSTRACT
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 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
The coding region determinant-binding protein (CRD-BP) binds in vitro to c-myc mRNA and is thought to stabilize the mRNA and increase c-Myc protein abundance. The CRD-BP gene has 15 exons and 14 introns, is single-copy, and is located on chromosome 11 in mice and 17 in humans, close to HER-2/neu. The CRD-BP gene is moderately amplified in 12 of 40 human breast cancers; it is highly amplified in 2 others (14.4 and 20 copies). Despite their proximity, CRD-BP and HER-2/neu genes can be amplified independently. Amplification of a gene that might up-regulate c-Myc abundance could accelerate breast cancer.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
c-myc mRNA contains two separate instability elements, an AU-rich determinant in its 3' untranslated region and a purine-rich ~250 nucleotide determinant in its coding region (the CRD3 ; 1 , 2 ). These determinants account for the short cytoplasmic half-life of c-myc mRNA. We have purified and characterized a c-myc CRD-BP based on its ability to bind to CRD RNA in vitro (1 , 3 , 4) . Cell-free mRNA decay experiments indicate that the CRD-BP functions as a shield to protect c-myc mRNA from rapid degradation and thereby to prolong its half-life. If the CRD-BP also protects c-myc mRNA in cells, its presence should increase c-Myc protein abundance and accelerate cell replication. The CRD-BP is orthologous to several proteins that bind to other mRNAs, including chicken ß-actin (5) and human insulin-like growth factor II (6) . It is also related to a human protein overexpressed in pancreatic cancer (KOC; 7 ), a human hepatocellular carcinoma autoantigen (p62; 8 ), and several developmentally regulated Xenopus proteins (9, 10, 11) . The potential relationship between the CRD-BP and human cancer arose from our finding that the CRD-BP is abundantly expressed in rat fetal life and in neoplastic cell lines but is undetectable in normal adult rat tissues (12) . These data suggested the CRD-BP is an oncofetal protein. Here, we describe the organization of the mouse CRD-BP gene, its localization in mouse and human chromosomes, and its amplification in a subset of human breast cancer patients.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Gene Mapping.
The cloning and sequencing of mouse CRD-BP cDNA has been described (3) . Mouse and human BACs containing the CRD-BP gene were obtained from Genome Systems and Research Genetics, respectively. For the mouse gene, an 129/SvJ genomic library was screened by PCR using CRD-BP-specific primers, and the gene was characterized by Southern blotting, PCR, and sequencing of a BAC clone. BAC DNA or genomic DNA from NIH3T3 cells or from C3H AhB1 mouse tails was digested with restriction enzymes, transferred to nitrocellulose, and probed with either exon-specific oligomers or CRD-BP cDNA fragments. Intron sizes were determined using PCR with BAC DNA as template and exon-specific oligomers as primers. In some cases, intron products were fully sequenced or were digested with restriction enzymes to verify restriction enzyme sites. Intron/exon junctions were sequenced with the ABI Big Dye PCR sequencing kit and an ABI 377 sequencing instrument.

FISH.
Normal mouse embryo fibroblasts (129/SvJ x C57BL/6 F1) or human peripheral blood cells were cultured and harvested to produce metaphase slides (13) . Human chromosomes were GTL banded as described (13) . Digoxigenin-labeled probes (Oncor) were used to detect mouse chromosome 11, the human chromosome 10 centromere, and genes for HER-2/neu, c-myc, RARA, and MPO. Each probe was visualized using rhodamine-conjugated anti-digoxigenin antibodies. To prepare CRD-BP probes for FISH, BAC clones containing the human or mouse CRD-BP gene were nick translated in reactions containing fluorescein-12-dUTP. Each probe was suspended in 10 µl of Oncor probe or Hybrisol VII (Oncor) and placed on dehydrated metaphase slides, which were sealed, heated to 75°C for 3 min to denature the probes, and hybridized at 37°C for l6–20 h in a humidified chamber. Slides were washed three times (5 min each) in 50% formamide in 2x SSC (1x SSC = 0.15 M NaCl, 0.015 M sodium citrate) at 45°C, twice (5 min each) in 2x SSC at 45°C, and once briefly in phosphate-buffered detergent (l00 mM sodium phosphate, 0.1% NP40, pH 7.4). Slides were counterstained with 4',6-diamidino-2-phenylindole and analyzed on an Olympus B-MAX fluorescent microscope equipped with a filter wheel and Applied Imaging software.

To analyze paraffin-embedded breast tumors, three sections of 4 µm were cut from paraffin blocks and mounted on Superfrost Plus Microscope Slides (Fisher). One slide from each specimen was stained with H&E to identify cancer and normal cells. The other slides were baked on a 65°C hot plate for 18 h and then deparaffinized in three changes (5 min each) of Hemo-De (Fisher), followed by two changes (2 min each) of absolute ethanol. Slides were pretreated with 1 M sodium thiocyanate at 43°C for 15 min, rinsed in water, incubated in 0.125 mg/ml Protein Digesting Enzyme (Ingen) in 2x SSC at 37°C for 30–45 min, washed in 2x SSC, and dehydrated. Probe (10 µl) was placed onto the specimen, which was then covered with an 18 x 18-mm coverslip and sealed. DNA was denatured at 75°C for 15 min, and hybridization, washing, and counterstaining were performed as above. Fluorescent signals per nucleus were counted in at least 40 tumor cells and 40 normal cells per case. CRD-BP gene amplification was based on an average of 2.5 or more signals per cell; HER-2/neu amplification was based on 3.5 or more signals per cell. When both CRD-BP and HER-2/neu gene copies exceeded 2.5, ploidy was assessed using the chromosome 10 centromere probe, and gene signal counts were corrected for polyploidy, when indicated by increased copies of chromosome 10.


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
The mouse CRD-BP gene is ~40 kb in length and contains 15 exons and 14 introns (Fig. 1Citation ). The CRD-BP itself contains three motifs that are present in other RNA-binding proteins: two RRMs, an RGG box, and four KH domains (3) . None of the RRM or KH motifs is encoded by any single exon, although the boundaries of the first RRM and of KH domain 3 coincide with intron-exon boundaries. The size of intron 2 has not been defined but is at least 16 kb. By comparing Southern blots of DNA from 129/SvJ and C3H mice, the CRD-BP gene contains at least two BamHI polymorphisms, one in intron 7 and the other in intron 9 (Fig. 1ACitation ).



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  		Fig. 1. Organization of the mouse CRD-BP gene. A, gene map. A mouse BAC clone was analyzed by Southern blotting and PCR to generate the map. Lines, flanking DNA and introns; rectangles, exons. A, Avr II; B, BamHI; Bg, BglII; E, EcoRI. ATG and TGA designate the translation start and stop sites, respectively. The sizes of exon 1 and intron I have not been determined. Dagger symbols, polymorphic BamHI sites. B, mRNA map. The relationship between exons and CRD-BP mRNA is indicated. Lines, 5'- and 3'-untranslated regions; rectangles, coding region. Exon 1 contains at least 174 bp. C, protein map. The abbreviations denote RNA-binding motifs that are characteristic of this and other RNA-binding proteins. M, the start methionine; *, COOH terminus.

 
FISH analysis was performed to localize the CRD-BP gene in normal mouse and human cell chromosomes. In mouse cells, analysis with a chromosome 11 paint probe (red) plus a fluorescein-labeled CRD-BP probe (green) visualized the CRD-BP gene on chromosome 11 (Fig. 2Citation A). In human cells, the CRD-BP gene resides on chromosome 17q21.3 (Fig. 2 and CCitation ). The gene is distal to the HER-2/neu gene at 17q11.2–12 and to RARA at l7q21.1 and is proximal to MPO at 17q23.1 (Fig. 2Citation C, bottom). The human CRD-BP gene was recently mapped to a region of chromosome 17 containing a gene thought to contribute to some cases of type 1 von Willebrand disease gene and is probably orthologous to the ß-actin mRNA zipcode-binding protein gene (5 , 14) .



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  		Fig. 2. Localization by FISH of the CRD-BP gene in mouse and human chromosomes. A, mouse. Metaphase spreads from normal mouse embryo fibroblasts (Sv129 x C57B16 F1) were analyzed with a fluorescein-labeled mouse CRD-BP gene probe (green) and a rhodamine-labeled mouse chromosome 11 paint probe (red). B, human. Metaphase spreads from normal human blood lymphocytes were analyzed with a fluorescein-labeled human CRD-BP gene probe (green) and a digoxigenin-labeled RARA gene probe (red). This and other digoxigenin-labeled probes were detected with a rhodamine-conjugated anti-digoxigenin antibody. C, Top, detail of human chromosome 17 showing the CRD-BP gene signal (green) next to the same chromosome 17 banded with GTL and a chromosome 17 ideogram. Bottom, copies of chromosome 17 hybridized with the green CRD-BP gene probe and (from left to right) with red probes for HER-2/neu, MPO, and RARA genes, respectively.

 
Three observations prompted us to use FISH to determine whether the CRD-BP gene is amplified in human tumors: (a) the proximal long-arm of human chromosome l7 contains several genes that are mutated, deleted, or amplified in cancer. BRCA-1 is located at 17q21, whereas HER-2/neu is located at 17q1l; (b) genes encoding hKOC and p62, both of which are related to the CRD-BP gene, are overexpressed in some pancreatic cancers and hepatocellular carcinomas, respectively (7 , 8) ; and (c) as determined by Western blotting, the CRD-BP is abundantly expressed in fetal tissues and in cancer cell lines but is undetectable in adult tissues (12) . This latter observation suggests that the CRD-BP might be an oncofetal protein. If so, its overexpression in human cancers could contribute to cancer cell survival/replication, because the CRD-BP is thought to enhance c-Myc protein expression, and c-Myc protein promotes cell replication.

FISH was performed using 40 breast cancer samples, and the CRD-BP gene was amplified in 14 of these (Figs. 3Citation and 4). In two cases, the gene was highly amplified (14.4 and 20 copies) and appeared to be on double-minute chromosomes (Fig. 3Citation ). The significance of this observation is underscored by the fact that only the tumor cells in each sample contained amplified CRD-BP genes. For example, the large tumor cells shown in Fig. 3ACitation have amplified CRD-BP genes (large arrow), whereas the surrounding smaller normal cells do not (small arrow). For comparison, an H&E section showing large, multinucleated tumor cells surrounded by smaller nonneoplastic cells is shown in Fig. 3BCitation . The CRD-BP gene was moderately amplified in another 12 breast cancer cases, when signal number was corrected for ploidy (Fig. 4Citation ). The HER-2/neu gene was coamplified in 7 of the 14 cases in which the CRD-BP gene was amplified, whereas the CRD-BP gene alone was amplified in the other seven cases. Therefore, amplification of these genes can occur independently, despite their proximity on chromosome 17. In both cases with highly amplified CRD-BP genes, the HER-2/neu gene was also amplified.



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  		Fig. 3. CRD-BP gene amplification in human breast cancer. A, FISH. Cells from a breast cancer patient with high CRD-BP gene amplification were analyzed with fluorescein-labeled human CRD-BP probe (green). The tumor cells with amplified genes (large arrow) are larger and more irregular than the adjacent normal cells (small arrow). B, H&E section. Large, multinucleolated tumor cells are visible in the center of the field.

 


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  		Fig. 4. CRD-BP and HER-2/neu gene copy number in 40 cases of invasive breast cancer, including 32 with infiltrating ductal carcinoma (IDC) and five with infiltrating lobular carcinoma (ILC). Of the remaining cases (Other), two were medullary carcinoma and one was comedo. The mean copy number of each gene is shown under each amplification category and is based on the 35 cases that are diploid, as determined using chromosome 10 copy number.

 
On the basis of these 40 cases, the CRD-BP gene is amplified in approximately one-third of human breast cancers. We do not yet know whether the CRD-BP itself is overexpressed in human breast cancer or other cancers or whether CRD-BP overexpression increases c-Myc protein abundance. However, it seems significant that CRD-BP gene amplification can occur without concomitant HER-2/neu amplification. Future studies will need to address these issues, as well as whether CRD-BP overexpression, with or without amplification/overexpression of c-myc or HER-2/neu, affects the course of breast cancer, especially in those patients with poor outcomes despite otherwise favorable prognostic indicators. CRD-BP overexpression in cancer tissue, with little or no expression in normal surrounding tissue, could be a useful prognostic/diagnostic indicator, as well as a potential therapeutic target. Moreover, having mapped the structural features of the CRD-BP gene, it becomes feasible to design transgenic animal experiments to assess the in vivo function of the protein using transgenic and gene knockout animal models.


   Acknowledgments
 
We thank Dr. Luis de las Casas for help in evaluating breast cancer slides and Tim Davis for technical help preparing metaphase spreads and G-banding. J. R. also acknowledges the assistance and encouragement of Dr. John E. Niederhuber.


   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 This work was supported by National Cancer Institute Grants R01-CA78710 (to J. R.), P30-CA-07175 (Cancer Center Support Grant to the McArdle Laboratory), and T32-CA09681 (to G. D.) and by a grant from the University of Wisconsin Robert Draper Technology Innovation Fund (to J. R.). Back

2 To whom requests for reprints should be addressed, at University of Wisconsin-Madison, McArdle Laboratory for Cancer Research, 1400 University Avenue, Madison, WI 53706. Phone: (608) 262-3413; Fax: (608) 262-2824; E-mail: ross{at}oncology.wisc.edu Back

3 The abbreviations used are: CRD, c-myc mRNA coding region determinant; CRD-BP, CRD-binding protein; BAC, bacterial artificial chromosome; FISH, fluorescence in situ hybridization; RRM, RNA recognition motif; KH, hnRNP K homology; MPO, myeloperoxidase; RARA, retinoic acid receptor {alpha}. Back

Received 12/16/99. Accepted 4/11/00.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

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  3. Doyle G. A., Betz N. A., Leeds P. F., Fleisig A. J., Prokipcak R. D., Ross J. The c-myc coding region determinant-binding protein: a member of a family of KH domain RNA-binding proteins. Nucleic Acids Res., 26: 5036-5044, 1998.[Abstract/Free Full Text]
  4. Prokipcak R. D., Herrick D. J., Ross J. Purification and properties of a protein that binds to the C-terminal coding region of human c-myc mRNA. J. Biol. Chem., 269: 9261-9269, 1994.[Abstract/Free Full Text]
  5. Ross A. F., Oleynikov Y., Kislauskis E. H., Taneja K. L., Singer R. H. Characterization of a ß-actin mRNA zipcode-binding protein. Mol. Cell. Biol., 17: 2158-2165, 1997.[Abstract]
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