- Research article
- Open Access
- Open Peer Review
Alterations of BCCIP, a BRCA2 interacting protein, in astrocytomas
© Liu et al; licensee BioMed Central Ltd. 2009
- Received: 29 October 2008
- Accepted: 4 August 2009
- Published: 4 August 2009
Loss of heterozygosity of chromosome 10q26 has been shown to be associated with the aggressiveness of astrocytic tumors (or astrocytomas), but the responsible gene(s) residing in this region has not been fully identified. The BCCIP gene is located at chromosome 10q26. It encodes a BRCA2 and CDKN1A (p21) interacting protein. Previous studies have shown that down-regulation of BCCIP impairs recombinational DNA repair, G1/S cell cycle checkpoint, p53 trans-activation activity, cytokinesis, and chromosome stability, suggesting a potential role of BCCIP in cancer etiology. In this study, we investigated whether BCCIP is altered in astrocytomas.
Genomic DNA from 45 cases of grade IV astrocytic tumor (glioblastoma) tissues and 12 cases of normal tissues were analyzed by quantitative PCR. The BCCIP protein expression in 96 cases of grade II–IV astrocytic tumors was detected by immunohistochemistry (IHC). IHC staining of glial fibrillary acid protein (GFAP), a marker for astrocytic cells, was used to identify cells of the astrocytic lineage.
We found that BCCIP protein is expressed in normal cells with positive staining of GFAP. However, BCCIP protein expression was not detectable in ~45% of all astrocytic tumors, and in > 60% in the grade IV glioblastoma. About 45% glioblastoma have significant (p < 0.01) reduction of BCCIP gene copy number when compared to normal DNA. Furthermore, the frequency of lacking BCCIP expression is associated with the aggressiveness of astrocytic tumors.
Our data implicate a role of BCCIP in astrocytic tumorigenesis, and lack of BCCIP may be used as a marker for astrocytomas.
- Brain Tumor
- Glial Fibrillary Acid Protein
- Astrocytic Tumor
- Brain Tumor Survival
Astrocytic tumor, or astrocytoma, is one of the most lethal forms of brain cancer although they rarely metastasize. Improvement of astrocytoma interventions requires further understanding on the genetic alterations associated with these tumors. Loss of heterozygosity (LOH) of chromosome 10q (especially region 10q25.3–26.2) is frequently associated with astrocytoma [1–11]. LOH on chromosome 10q26 is highly correlated with a poor prognosis for astrocytoma [1–7, 9–12], and perhaps is the one of the most reliable prognosis markers associated with a worse outcome [8, 9, 13]. Thus, identifying the gene(s) in this region associated with this form of brain tumor is of critical importance for astrocytoma intervention. In addition to brain tumor, LOH of 10q26 has been shown to be associated with prostate cancers, endometrial cancers, and lung cancers [14–17], further suggesting the importance of identifying the tumor related gene(s) on 10q26.
Genomic instability is a major driving force for tumor progression. The BRCA2 gene plays critical roles in the maintenance of genomic stability by regulating homologous recombination, and BRCA2 defects are associated with predisposition to various human cancer. Although mutation of BRCA2 itself is involved in only a small population of human cancer, the germline BRCA2 mutations are highly penetrative to cancer. This suggests that the entire molecular pathway of BRCA2 are critical for cancer prevention, and other proteins related to BRCA2 may contribute to additional tumors . Thus identifications and analyses of novel BRCA2 interacting protein may provide unique opportunities to identify additional genetic factors involved in tumorigenesis. We and others have previously reported BCCIP as a BRCA2 and CDKN1A  interacting protein [20–23]. We have shown that the chromatin bound fraction of BCCIP co-localizes with BRCA2 and contributes to BRCA2 and RAD51 nuclear focus formation . A ~50% down-regulation of BCCIP is sufficient to inhibit homologous recombination, and both the BRCA2 and p21 interaction domains of BCCIP play a role in regulating homologous recombination [22, 24, 25]. Furthermore, BCCIP has been shown to play a role in supporting p53 transcription activity, and the completion of cytokinesis during mitosis [26, 27]. All these support a critical role of BCCIP in the maintenance of genomic stability.
The human BCCIP gene is located at 10q26.1 , and a recent report suggested that BCCIP may be absent in at least one astrocytoma cell line . We previously showed that the A172 astrocytic brain tumor cell line has reduced expression of BCCIPα . Given that BCCIP is involved in important processes relevant to the maintenance of genome stability and its localization at 10q26, we investigated the possibility of BCCIP alterations in more than 100 cases of astrocytomas. Because brain tumor in the astrocyte lineage are the most common type [29, 30], we emphasized our analyses on the astrocytic tumors including the grade IV glioblastoma multiforme. We found that BCCIP is down-regulated in a major portion of these brain tumors. Furthermore, BCCIP down-regulation is correlated with the aggressiveness of astrocytomas. These data suggest BCCIP alteration as a new marker for astrocytomas.
Quantitative Real-Time PCR detection of BCCIP copy number
A total of 45 cases of anonymous genomic DNA were isolated from grade IV astrocytoma as previously reported [5, 31]. Twelve cases of DNA from peripheral blood leukocytes were used as control for normal BCCIP gene dosage determination. Real-time PCR was done using the SYBR Green strategy with a DNA Engine Opticon™ 2 Real-Time Detection System (M J Research Inc. South San Francisco, CA). Each pair of primers was optimized to amplify only the anticipated PCR products, which were verified by DNA sequencing and melting curve analysis. The primers for BCCIP are as follows: exon 5: 5'-TGC TTT CTA GGG TAC CCA GTG-3' (forward) and 5'-CCA CAG GCT TGG TGG TGT C-3'(reverse, 129 bp); exon 6: 5'-GGC ACA CAG AAC CAA TAA GCC-3' (forward) and 5'-CAT TTG CAA ACA TTA ACG CAG C-3' (reverse, 136 bp); exon 7: 5'-TCA ACT ACT CAG TGC AGG AGG AG-3' (forward) and 5'-CAG TTT ATC CAT GAT TTC GTT CAT C-3' (reverse, 135 bp); exon 9: 5'-AAG TGA CAG CCC TGG TTT CTC-3' (forward) and 5'-ATG AGC CTC CTA AAT CCC TGA C-3' (reverse, 130 bp). To normalize the copy number of BCCIP gene, the copy number of glyseraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal control. The primers for GAPDH are: 5'-AAC GTG TCA GTG GTG GAC CTG-3' (forward) and 5'-AGT GGG TGT CGC TGT TGA AGT-3' (reverse, 160 bp), as validated and described previously [5, 32]. This pair of primers amplifies a single band as confirmed by melting curve analysis with the DNA Engine Opticon™ 2 Real-Time Detection System (M J Research Inc. South San Francisco, CA), and confirmed to be the coding gene of GAPDH by DNA sequencing. To our knowledge, this pair of primer does not amply GAPDH pseudogenes. In each PCR analyses, we used 25 μl of reaction volume containing 4 μl of DNA, 100 μM each of the primers, and 12.5 μl of 2× master mix from DyNAmo HS SYBR Green qPCR kit (Finnzymes). Standard curve to calibrate DNA concentration was performed for all amplifications for each pair of primers. The PCR reaction tubes were first incubated for 15 minutes at 95°C, followed by 40 cycles of 30 seconds at 95°C, 20 seconds at optimized annealing temperature depending on the primers, and 20 seconds at 72°C.
Antibodies and Immunohistochemistry of BCCIP and GFAP in brain tumors
Rabbit anti-BCCIPα/β antibodies were reported previously . Paraffin embedded brain tumor tissue array slides (Catalog No GL801, BS17001, and BS17014) were purchased from US Biomax (Rockvile, MD). The core diameter is 1.5 mm, and the slides have thickness of 5 μm. The pathological grade of tumor on the array were provided by the slide supplier, and later confirmed by us when the slides were evaluated. The astrocytoma grade II–IV in pathology diagnosis is equivalent to low-grade moderately-differentiated astrocytoma, anaplastic astrocytoma, and undifferentiated glioblastoma multiforme respectively. These slides originally contain more than 100 cases of independent astrocytoma, 12 cases of oligodendroglioma, and 5 cases of ependymomas. Some of the cases were eliminated from data analysis due to lack of tumor tissues on the cores of the particular cases. This was caused by tissue detachment from the slides during the staining process, or because the presence of tumor tissue cannot be verified. Thus, a total 96 cases of astrocytomas, 6 cases of oligodendrogliomas, and 5 cases of ependymomas are reported here. Because objective of this study is to perform a retrospective determination on whether BCCIP is altered in existing specimens without contacting with living individual, no information on the patient identities and clinical outcomes are available for the investigators, approval for human subject research was deemed unnecessary.
The astrocytomas are in the astrocytic lineage, and the astrocytic cells often express a unique marker glial fibrillary acid protein (GFAP). Based on staining of non-tumor brain tissue, BCCIP is not uniformly expressed in brain tissue, but its expression can be detected in GFAP positive cells (see Results section). Therefore, we stained GFAP to identify the astrocytic tumor cells in the sections. Double staining of the same slide with GFAP and BCCIP turned out to be challenging with the available antibodies. Thus, two neighboring serial sections of these slides were stained with anti-GFAP monoclonal antibody (Chemicon International, Temecula, CA) and anti-BCCIP antibody respectively using routine immunohistochemistry (IHC) protocols. Briefly, slides were de-paraffinized with xylene for 10 min, and repeated three times. The antigen was retrieved in citrate acid buffer (pH6.5) by steaming in a rice cooker for 20 min. Following antigen retrieval, the endogenous peroxidase activity was blocked at room temperature by 20 minutes of incubation with 1% H2O2 in methanol. The slides were blocked with 5% milk in TBS-T (25 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.1% Tween20) for 30 min at room temperature, and then incubated with 1:100 diluted affinity-purified rabbit polyclonal anti-BCCIP antibodies for 3 hrs at room temperature. This BCCIP antibody has been reported previously .
Following 3 times wash with TBS-T, the slides were incubated for 1 hr at room temperature with anti-Rabbit IgG secondary antibody (1:100) that was conjugated with horseradish peroxidase. The chromogenic substrate diaminobenzidine (DAB) was used as a chromogen to stain BCCIP positive cells (brown color). Haematoxylin was used as contrast staining for BCCIP negative cell nuclei (blue color). After mounting, the slides were observed under microscope. When the BCCIP nuclear stain was found in less than 5% of tumor cells, the case was scored as BCCIP negative. When more than 5% tumor cells are stained BCCIP positive, the case was considered BCCIP positive. For GFAP staining and evaluation, the same as BCCIP was used, except anti-GFAP monoclonal antibody was used as first antibody, and anti- mouse IgG (1:100) was used as the secondary antibody which was conjugated with horseradish peroxidase.
Reduction of BCCIP gene dosage in brain tumors
Loss of BCCIP protein expression in brain tumor
Number of cases analyzed by IHC on tissue array
Cytogenetic and LOH analyses have suggested that at least three distinct regions of the long arm of chromosome 10 are related to brain tumorigenesis: 10q23.3, 10q24–25, and 10q25.3–26.2. The tumor susceptibility gene located at 10q23.3 has been identified as the PTEN (phosphatase and tension homologue detected on chromosome TEN) or MMAC (mutated in multiple advanced cancers) gene. PTEN/MMAC protein has two distinct structural domains, the phosphatase domain and a C2 domain that binds phospholipid membranes in vitro . PTEN mutations have been identified in a variety of human cancers [38–41]. A second tumor susceptibility gene is located at 10q24–25. The c-Myc, Max homologous gene MXI1 is located in this region [17, 42–50].
A putative tumor susceptibility gene DMBT1 (Deleted in Malignant Brain Tumors) has been identified in 10q25.3–26.2. . DMBT1 is homologous to the scavenger receptor cysteine-rich (SRCR) superfamily of proteins. Since it is deleted in a large proportion of brain tumors, it has been suggested as a candidate for the tumor susceptibility gene in this region. However, expression of DMBT1 in tumor cells has little effect on tumor cell growth or tumor associated phenotypes [4, 52–54]. This opens the possibility that additional genes in this region may be relevant to brain tumorigenesis. Considering that: 1) BCCIP interacts with BRCA2 and p21, 2) BCCIP plays a role in homologous recombination, cell cycle regulation, p53 transcription activity, and chromosome instability [19–24, 26, 27], 3) BCCIP expression is absent in a significant portion of astrocytomas (Figure 2), and 4) the lack of BCCIP expression is correlated with the aggressiveness of astrocytomas (Figure 3), we suggest that BCCIP is a strong candidate for the tumor suppressor gene in the chromosome 10q26 region. However, additional investigation, preferably with animal knock-out or knock-down models, is needed to conclude whether BCCIP defects directly cause brain tumor. It should be pointed out that the 10q26.2 region has been implicated in many other cancer types. The role of BCCIP in other cancer types warrants additional investigations.
Mutation of p53 has been reported in 31% of brain tumor, but LOH of the 10q region has been reported in 69% of brain tumor . Despite that majority of the brain tumor harbors wild type p53, brain tumors are well known for their radiation resistance. We reported that in the absence of BCCIP, the transactivation activity of wild type p53 protein is not sustainable . Down-regulation of BCCIP leads to a resistance to ionizing radiation of HCT116 cells with wild type p53 . It has been recently shown that lack of BCCIP in p53 wild type laryngeal cancer is associated with poor progress in response to radiation therapy . Here we show that a significant portion of astrocytomas has down-regulation of BCCIP. It would be interesting to determine whether the lack of BCCIP expression plays a role in the radiation resistance for these brain tumors with wild type p53.
The dependence of p53 function on BCCIP makes an ideal argument that BCCIP may function as a tumor suppressor, and BCCIP defects are responsible for astrocytoma aggression and resistant to radiation therapy. Because BCCIP has also been shown to be required for completion of mitosis, and severe knockdown of BCCIP resulted in growth retardation in other cell types , it remains to be addressed how loss of BCCIP expression may lead to brain tumor survival. Thus, it is likely that lack of BCCIP expression needs to be coupled with additional genetic alterations for tumor cells to be viable and remain aggressive. If this is true, then identification of these additional genetic factor(s) enabling BCCIP defective cells to survive is a critical issue for future studies.
We found that BCCIP expression is down-regulated in a significant portion of astrocytomas, and the loss of BCCIP expression is more frequent in the aggressive form of astrocytomas. These data suggest BCCIP as a potential marker for brain tumorigenesis.
This research was supported by National Institute of Health grants CA115488.
- Rasheed BK, Fuller GN, Friedman AH, Bigner DD, Bigner SH: Loss of heterozygosity for 10q loci in human gliomas. Genes Chromosomes Cancer. 1992, 5: 75-82. 10.1002/gcc.2870050111.View ArticlePubMedGoogle Scholar
- Karlbom AE, James CD, Boethius J, Cavenee WK, Collins VP, Nordenskjold M, Larsson C: Loss of heterozygosity in malignant gliomas involves at least three distinct regions on chromosome 10. Hum Genet. 1993, 92: 169-74. 10.1007/BF00219686.View ArticlePubMedGoogle Scholar
- Balesaria S, Brock C, Bower M, Clark J, Nicholson SK, Lewis P, de Sanctis S, Evans H, Peterson D, Mendoza N, et al: Loss of chromosome 10 is an independent prognostic factor in high-grade gliomas. Br J Cancer. 1999, 81: 1371-7. 10.1038/sj.bjc.6693403.View ArticlePubMedPubMed CentralGoogle Scholar
- Steck PA, Lin H, Langford LA, Jasser SA, Koul D, Yung WK, Pershouse MA: Functional and molecular analyses of 10q deletions in human gliomas. Genes Chromosomes Cancer. 1999, 24: 135-43. 10.1002/(SICI)1098-2264(199902)24:2<135::AID-GCC6>3.0.CO;2-A.View ArticlePubMedGoogle Scholar
- Fujisawa H, Reis RM, Nakamura M, Colella S, Yonekawa Y, Kleihues P, Ohgaki H: Loss of heterozygosity on chromosome 10 is more extensive in primary (de novo) than in secondary glioblastomas. Lab Invest. 2000, 80: 65-72. 10.1038/labinvest.3780009.View ArticlePubMedGoogle Scholar
- Daido S, Takao S, Tamiya T, Ono Y, Terada K, Ito S, Ouchida M, Date I, Ohmoto T, Shimizu K: Loss of heterozygosity on chromosome 10q associated with malignancy and prognosis in astrocytic tumors, and discovery of novel loss regions. Oncol Rep. 2004, 12: 789-95.PubMedGoogle Scholar
- Hill C, Hunter SB, Brat DJ: Genetic markers in glioblastoma: prognostic significance and future therapeutic implications. Adv Anat Pathol. 2003, 10: 212-7. 10.1097/00125480-200307000-00004.View ArticlePubMedGoogle Scholar
- Ohgaki H: Genetic pathways to glioblastomas. Neuropathology. 2005, 25: 1-7. 10.1111/j.1440-1789.2004.00600.x.View ArticlePubMedGoogle Scholar
- Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schuler D, Probst-Hensch NM, Maiorka PC, et al: Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004, 64: 6892-9. 10.1158/0008-5472.CAN-04-1337.View ArticlePubMedGoogle Scholar
- Merlo A: Genes and pathways driving glioblastomas in humans and murine disease models. Neurosurg Rev. 2003, 26: 145-58.View ArticlePubMedGoogle Scholar
- Maier D, Zhang Z, Taylor E, Hamou MF, Gratzl O, Van Meir EG, Scott RJ, Merlo A: Somatic deletion mapping on chromosome 10 and sequence analysis of PTEN/MMAC1 point to the 10q25–26 region as the primary target in low-grade and high-grade gliomas. Oncogene. 1998, 16: 3331-5. 10.1038/sj.onc.1201832.View ArticlePubMedGoogle Scholar
- Ohgaki H, Kleihues P: Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 2005, 64: 479-89.View ArticlePubMedGoogle Scholar
- Homma T, Fukushima T, Vaccarella S, Yonekawa Y, Di Patre PL, Franceschi S, Ohgaki H: Correlation among pathology, genotype, and patient outcomes in glioblastoma. J Neuropathol Exp Neurol. 2006, 65: 846-54. 10.1097/01.jnen.0000235118.75182.94.View ArticlePubMedGoogle Scholar
- Ittmann M: Allelic loss on chromosome 10 in prostate adenocarcinoma. Cancer Res. 1996, 56: 2143-7.PubMedGoogle Scholar
- Ittmann MM: Chromosome 10 alterations in prostate adenocarcinoma (review). Oncol Rep. 1998, 5: 1329-35.PubMedGoogle Scholar
- Peiffer SL, Herzog TJ, Tribune DJ, Mutch DG, Gersell DJ, Goodfellow PJ: Allelic loss of sequences from the long arm of chromosome 10 and replication errors in endometrial cancers. Cancer Res. 1995, 55: 1922-6.PubMedGoogle Scholar
- Petersen S, Wolf G, Bockmuhl U, Gellert K, Dietel M, Petersen I: Allelic loss on chromosome 10q in human lung cancer: association with tumour progression and metastatic phenotype. Br J Cancer. 1998, 77: 270-6.View ArticlePubMedPubMed CentralGoogle Scholar
- Couzin J: The twists and turns in BRCA's path. Science. 2003, 302: 591-3. 10.1126/science.302.5645.591.View ArticlePubMedGoogle Scholar
- Meng X, Lu H, Shen Z: BCCIP functions through p53 to regulate the expression of p21Waf1/Cip1. Cell Cycle. 2004, 3: 1457-62.View ArticlePubMedGoogle Scholar
- Liu J, Yuan Y, Huan J, Shen Z: Inhibition of breast and brain cancer cell growth by BCCIPalpha, an evolutionarily conserved nuclear protein that interacts with BRCA2. Oncogene. 2001, 20: 336-45. 10.1038/sj.onc.1204098.View ArticlePubMedGoogle Scholar
- Ono T, Kitaura H, Ugai H, Murata T, Yokoyama KK, Iguchi-Ariga SM, Ariga H: TOK-1, a novel p21Cip1-binding protein that cooperatively enhances p21-dependent inhibitory activity toward CDK2 kinase. J Biol Chem. 2000, 275: 31145-54. 10.1074/jbc.M003031200.View ArticlePubMedGoogle Scholar
- Lu H, Guo X, Meng X, Liu J, Allen C, Wray J, Nickoloff JA, Shen Z: The BRCA2-interacting protein BCCIP functions in RAD51 and BRCA2 focus formation and homologous recombinational repair. Mol Cell Biol. 2005, 25: 1949-57. 10.1128/MCB.25.5.1949-1957.2005.View ArticlePubMedPubMed CentralGoogle Scholar
- Meng X, Liu J, Shen Z: Inhibition of G1 to S cell cycle progression by BCCIP beta. Cell Cycle. 2004, 3: 343-8.PubMedGoogle Scholar
- Lu H, Yue J, Meng X, Nickoloff JA, Shen Z: BCCIP regulates homologous recombination by distinct domains and suppresses spontaneous DNA damage. Nucleic Acids Res. 2007, 35: 7160-7170. 10.1093/nar/gkm732.View ArticlePubMedPubMed CentralGoogle Scholar
- Wray J, Liu J, Nickoloff JA, Shen Z: Distinct RAD51 associations with RAD52 and BCCIP in response to DNA damage and replication stress. Cancer Research. 2008, 68: 2699-2707. 10.1158/0008-5472.CAN-07-6505.View ArticlePubMedPubMed CentralGoogle Scholar
- Meng X, Yue J, Liu Z, Shen Z: Abrogation of the transactivation activity of p53 by BCCIP down-regulation. J Biol Chem. 2007, 282: 1570-6. 10.1074/jbc.M607520200.View ArticlePubMedGoogle Scholar
- Meng X, Fan J, Shen Z: Roles of BCCIP in chromosome stability and cytokinesis. Oncogene. 2007, 26: 6253-60. 10.1038/sj.onc.1210460.View ArticlePubMedPubMed CentralGoogle Scholar
- Roversi G, Pfundt R, Moroni RF, Magnani I, van Reijmersdal S, Pollo B, Straatman H, Larizza L, Schoenmakers EF: Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines. Oncogene. 2006, 25: 1571-83. 10.1038/sj.onc.1209177.View ArticlePubMedGoogle Scholar
- Reifenberger G, Collins VP: Pathology and molecular genetics of astrocytic gliomas. J Mol Med. 2004, 82: 656-70. 10.1007/s00109-004-0564-x.View ArticlePubMedGoogle Scholar
- Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK: The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol. 2002, 61: 215-25. discussion 226–9.View ArticlePubMedGoogle Scholar
- Maier D, Comparone D, Taylor E, Zhang Z, Gratzl O, Van Meir EG, Scott RJ, Merlo A: New deletion in low-grade oligodendroglioma at the glioblastoma suppressor locus on chromosome 10q25–26. Oncogene. 1997, 15: 997-1000. 10.1038/sj.onc.1201209.View ArticlePubMedGoogle Scholar
- Watanabe T, Nakamura M, Yonekawa Y, Kleihues P, Ohgaki H: Promoter hypermethylation and homozygous deletion of the p14ARF and p16INK4a genes in oligodendrogliomas. Acta Neuropathol. 2001, 101: 185-9.PubMedGoogle Scholar
- Meng X, Liu J, Shen Z: Genomic structure of the human BCCIP gene and its expression in cancer. Gene. 2003, 302: 139-46. 10.1016/S0378-1119(02)01098-3.View ArticlePubMedGoogle Scholar
- Shih AH, Holland EC: Developmental neurobiology and the origin of brain tumors. J Neurooncol. 2004, 70: 125-36. 10.1007/s11060-004-2746-3.View ArticlePubMedGoogle Scholar
- Eng LF, Ghirnikar RS: GFAP and astrogliosis. Brain Pathol. 1994, 4: 229-37. 10.1111/j.1750-3639.1994.tb00838.x.View ArticlePubMedGoogle Scholar
- Fujisawa H, Kurrer M, Reis RM, Yonekawa Y, Kleihues P, Ohgaki H: Acquisition of the glioblastoma phenotype during astrocytoma progression is associated with loss of heterozygosity on 10q25-qter. Am J Pathol. 1999, 155: 387-94.View ArticlePubMedPubMed CentralGoogle Scholar
- Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P, Pavletich NP: Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell. 1999, 99: 323-34. 10.1016/S0092-8674(00)81663-3.View ArticlePubMedGoogle Scholar
- Rossi DJ, Weissman IL: Pten, tumorigenesis, and stem cell self-renewal. Cell. 2006, 125: 229-31. 10.1016/j.cell.2006.04.006.View ArticlePubMedGoogle Scholar
- Chow LM, Baker SJ: PTEN function in normal and neoplastic growth. Cancer Lett. 2006, 241: 184-96. 10.1016/j.canlet.2005.11.042.View ArticlePubMedGoogle Scholar
- Stiles B, Groszer M, Wang S, Jiao J, Wu H: PTENless means more. Dev Biol. 2004, 273: 175-84. 10.1016/j.ydbio.2004.06.008.View ArticlePubMedGoogle Scholar
- Leslie NR, Downes CP: PTEN function: how normal cells control it and tumour cells lose it. Biochem J. 2004, 382: 1-11. 10.1042/BJ20040825.View ArticlePubMedPubMed CentralGoogle Scholar
- Scott DK, Straughton D, Cole M, Bailey S, Ellison DW, Clifford SC: Identification and analysis of tumor suppressor loci at chromosome 10q23.3–10q25.3 in medulloblastoma. Cell Cycle. 2006, 5: 2381-9.View ArticlePubMedGoogle Scholar
- Ariyanayagam-Baksh SM, Baksh FK, Swalsky PA, Finkelstein SD: Loss of heterozygosity in the MXI1 gene is a frequent occurrence in melanoma. Mod Pathol. 2003, 16: 992-5. 10.1097/01.MP.0000087421.44975.1C.View ArticlePubMedGoogle Scholar
- Herbst RA, Podewski EK, Mommert S, Kapp A, Weiss J: PTEN and MXI1 allelic loss on chromosome 10q is rare in melanoma in vivo. Arch Dermatol Res. 1999, 291: 567-9. 10.1007/s004030050456.View ArticlePubMedGoogle Scholar
- Prochownik EV, Eagle Grove L, Deubler D, Zhu XL, Stephenson RA, Rohr LR, Yin X, Brothman AR: Commonly occurring loss and mutation of the MXI1 gene in prostate cancer. Genes Chromosomes Cancer. 1998, 22: 295-304. 10.1002/(SICI)1098-2264(199808)22:4<295::AID-GCC5>3.0.CO;2-Q.View ArticlePubMedGoogle Scholar
- Kuczyk MA, Serth J, Bokemeyer C, Schwede J, Herrmann R, Machtens S, Grunewald V, Hofner K, Jonas U: The MXI1 tumor suppressor gene is not mutated in primary prostate cancer. Oncol Rep. 1998, 5: 213-6.PubMedGoogle Scholar
- Wechsler DS, Shelly CA, Petroff CA, Dang CV: MXI1, a putative tumor suppressor gene, suppresses growth of human glioblastoma cells. Cancer Res. 1997, 57: 4905-12.PubMedGoogle Scholar
- Kim SK, Ro JY, Kemp BL, Lee JS, Kwon TJ, Hong WK, Mao L: Identification of two distinct tumor-suppressor loci on the long arm of chromosome 10 in small cell lung cancer. Oncogene. 1998, 17: 1749-53. 10.1038/sj.onc.1202073.View ArticlePubMedGoogle Scholar
- Wang DS, Rieger-Christ K, Latini JM, Moinzadeh A, Stoffel J, Pezza JA, Saini K, Libertino JA, Summerhayes IC: Molecular analysis of PTEN and MXI1 in primary bladder carcinoma. Int J Cancer. 2000, 88: 620-5. 10.1002/1097-0215(20001115)88:4<620::AID-IJC16>3.0.CO;2-Z.View ArticlePubMedGoogle Scholar
- Delnatte C, Sanlaville D, Mougenot JF, Vermeesch JR, Houdayer C, Blois MC, Genevieve D, Goulet O, Fryns JP, Jaubert F, et al: MXI1, a putative tumor suppressor gene, suppresses growth of human glioblastoma cells. Am J Hum Genet. 2006, 78: 1066-74. 10.1086/504301.View ArticlePubMedPubMed CentralGoogle Scholar
- Mollenhauer J, Wiemann S, Scheurlen W, Korn B, Hayashi Y, Wilgenbus KK, von Deimling A, Poustka A: DMBT1, a new member of the SRCR superfamily, on chromosome 10q25.3–26.1 is deleted in malignant brain tumours. Nat Genet. 1997, 17: 32-9. 10.1038/ng0997-32.View ArticlePubMedGoogle Scholar
- Sasaki H, Betensky RA, Cairncross JG, Louis DN: DMBT1 polymorphisms: relationship to malignant glioma tumorigenesis. Cancer Res. 2002, 62: 1790-6.PubMedGoogle Scholar
- Sanson M, Leuraud P, Aguirre-Cruz L, He J, Marie Y, Cartalat-Carel S, Mokhtari K, Duffau H, Delattre JY, Hoang-Xuan K: Analysis of loss of chromosome 10q, DMBT1 homozygous deletions, and PTEN mutations in oligodendrogliomas. J Neurosurg. 2002, 97: 1397-401. 10.3171/jns.2002.97.6.1397.View ArticlePubMedGoogle Scholar
- Pang JC, Dong Z, Zhang R, Liu Y, Zhou LF, Chan BW, Poon WS, Ng HK: Mutation analysis of DMBT1 in glioblastoma, medulloblastoma and oligodendroglial tumors. Int J Cancer. 2003, 105: 76-81. 10.1002/ijc.11019.View ArticlePubMedGoogle Scholar
- Rewari A, Lu H, Parikh R, Yang Q, Shen Z, Haffty BG: BCCIP as a prognostic marker for radiotherapy of laryngeal cancer. Radiother Oncol. 2009, 90: 183-8. 10.1016/j.radonc.2008.10.020.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://0-www.biomedcentral.com.brum.beds.ac.uk/1471-2407/9/268/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.