17q21-q25 aberrations in breast cancer: combined allelotyping and CGH analysis reveals 5 regions of allelic imbalance among which two correspond to DNA amplification

Orsetti, Béatrice; Courjal, Frank; Cuny, Marguerite; Rodrı́guez, Carmen; Theillet, Charles

doi:10.1038/sj.onc.1203006

Cited by 56 publications

(37 citation statements)

References 22 publications

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“…The NHERF gene is mapped at 17q25, a region that undergoes frequent allelic loss in breast and ovarian cancer (Radford et al, 1995;Kalikin et al, 1996Kalikin et al, , 1997Plummer et al, 1997;Orsetti et al, 1999;Harkes et al, 2003). LOH involving this locus was determined with three highly polymorphic markers (D17S785, D17S801, and D17S1351) that neighbored the NHERF gene.…”

Section: Mutational Analyses Of Nherf Genementioning

confidence: 99%

NHERF (Na+/H+ Exchanger Regulatory Factor) gene mutations in human breast cancer

et al. 2004

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Yeast two-hybrid screening was used to explore novel proteins that interact with a breast tumor or metastasis suppressor, SYK (spleen tyrosine kinase). The screening yielded NHERF (Na + /H + exchanger regulatory factor, also known as NHERF1 or EBP-50) that binds to the interdomain B of SYK. NHERF is an estrogen-responsive gene that encodes an inhibitory factor for epithelial Na + /H + exchanger isoform 3 (NHE3). We found intragenic mutation of the NHERF gene accompanied by loss of heterzygosity (LOH) in B3% (3/85) of breast cancer cell lines and primary breast tumors. Mutations occurred at the conserved PDZ domains at NHERF NH 2 -terminus that bound to SYK, or at its COOH-terminus motif that binds to MERLIN, the product of Neurofibromatosis 2 (NF2) tumor suppressor gene. NHERF tumorigenic mutations decreased or abolished its interaction with SYK or MERLIN, suggesting a pathway link among these three molecules that may play a critical role in mammary neoplastic progression. Primary breast tumors with LOH at the NHERF locus had clinical presentations of higher aggressiveness, indicating that deregulated NHERF signaling may be associated with disease progression. Moreover, the LOH was inversely correlated with SYK promoter methylation, suggesting that NHERF and SYK may transduce a common suppressive signal. Taken together, the results indicated NHERF to be a candidate tumor suppressor gene in human breast carcinoma that may be interconnected to the SYK and MERLIN suppressors.

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Section: Mutational Analyses Of Nherf Genementioning

confidence: 99%

NHERF (Na+/H+ Exchanger Regulatory Factor) gene mutations in human breast cancer

et al. 2004

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“…In sporadic forms of breast cancer, a number of ampli®ed or deleted chromosome regions have been identi®ed using techniques, which test for allelic imbalance (Bieche et al, 1999;Bonsing et al, 2000;Orsetti et al, 1999;Osborne and Hamshere, 2000;Rodriguez et al, 2000;Sta et al, 2000). In high-grade breast cancer, chromosome regions that are ampli®ed leading to protein overexpression, often include genes coding ErbB2, c-Myc and Cyclin D1 (Brison, 1993).…”

Section: Introductionmentioning

confidence: 99%

Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice

et al. 2001

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Germline mutations in the tumor suppressor gene BRCA1 predispose women to breast cancer, however somatic mutations in the gene are rarely detected in sporadic cancers. To understand this phenomenon, we examined mouse models carrying conditional disruption of Brca1 in mammary epithelium in either p53 wild type (wt) or heterozygous backgrounds. Although a p53 +/7 mutation signi®cantly accelerated tumorigenesis, both strains developed mammary tumors in a stochastic fashion, suggesting that multiple factors, in addition to p53 mutations, may be involved in Brca1 related tumorigenesis. A unique feature of Brca1 mammary tumors is their highly diverse histopathology accompanied by severe chromosome abnormalities. The tumors also display extensive genetic/molecular alterations, including overexpression of ErbB2, c-Myc, p27 and Cyclin D1 in the majority of tumors, while they were virtually ERa and p16 negative. Translocations involving p53 were also identi®ed which lead to abnormal RNA and protein products. In addition, we generated cell lines from mammary tumors and found that the cells retained many of the genetic changes found in the primary tumors, suggesting that these genes may be players in Brca1-associated tumorigenesis. Despite their distinct morphology, all cultured tumor cells were Tamoxifen resistant but highly sensitive to Doxorubicin or girradiation, suggesting that these methods would be e ective in treatment of this disease. Oncogene (2001) 20, 7514 ± 7523.

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“…Evaluation of the CNVs for such genes is a starting point for investigations into the role of gene amplification in the colorectal carcinogenic process. Although a number of studies showed that the chromosome 17q21 region encompassing HER-2 was amplified in breast cancer samples (14)(15)(16)(17), the correlation between CNVs and HER-2 overexpression in CRC has yet to be elucidated. In this study, 134 CRC (adenocarcinomas) samples were collected for CNV analysis of HER-2.…”

Section: Discussionmentioning

confidence: 99%

“…The role of copy-number variations (CNVs) in various types of cancer has become a hot spot over the past few years (12,13). Studies using SNP arrays and aCGH have suggested that DNA amplification at chromosome position 17q21, the chromosomal locus of HER-2, is common in breast cancers (14)(15)(16)(17). However, the correlation between CNVs and HER-2 overexpression in CRC has yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

Copy number increase of HER-2 in colorectal cancers

et al. 2010

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Abstract. HER-2 is involved in genetic instability and is overexpressed in a number of human carcinomas, including colorectal cancer (CRC). The choromosomal locus of HER-2, 17q21, is frequently amplified in breast cancer, but the correlation between copy-number variations and HER-2 overexpression in CRC has yet to be elucidated. The functional impact of such regions requires extensive investigation in large numbers of CRC samples. Case-matched tissues of colorectal adenocarcinomas and adjacent normal epithelia (n=134) were included in this study. Quantitative PCR was performed to examine the copy number and mRNA expression of HER-2 in CRC. The results showed that copy number gains of HER-2 were detected in a relatively high percentage of CRC samples (35.1%, 47 out of 134). A positive correlation was noted between the copy number increase of HER-2 and tumor progression. Furthermore, copy number gains of HER-2 showed a positive correlation with mRNA overexpression in CRC. However, the expression levels of HER-2 mRNA were also enhanced in the group of CRC samples with unaltered copy numbers. In conclusion, the findings suggest that a copy number increase of HER-2 is a potential diagnostic indicator for CRC; whether alone or in combination with other markers.

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17q21-q25 aberrations in breast cancer: combined allelotyping and CGH analysis reveals 5 regions of allelic imbalance among which two correspond to DNA amplification

Cited by 56 publications

References 22 publications

NHERF (Na+/H+ Exchanger Regulatory Factor) gene mutations in human breast cancer

NHERF (Na+/H+ Exchanger Regulatory Factor) gene mutations in human breast cancer

Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice

Copy number increase of HER-2 in colorectal cancers

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