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ErbB2 copy number gain is associated with adverse outcome in canine mammary carcinoma.

ABSTRACT: Copy number gain (CNG) and/or protein overexpression of ErbB2 have been observed in human breast cancer patients and are associated with poor prognosis. Similarly, ErbB2 overexpression has also been observed in canine mammary carcinoma; however, data on ErbB2 copy number is limited. The purposes of this study were to evaluate ErbB2 copy number in dogs with mammary carcinoma and to investigate associations of ErbB2 CNG with ErbB2 expression, histological and clinical characteristics, and survival. DNA samples were isolated from 59 formalin-fixed paraffin-embedded canine mammary gland tissues (34 carcinoma, 14 adenoma, and 11 normal). Using a digital PCR assay, the ErbB2 copy number in these samples was determined as compared to a reference gene on canine chromosome 8. ErbB2 CNG was detected in 14/34 (41%) carcinomas and 2/14 (14%) adenomas. ErbB2 overexpression was observed in 3/34 (9%) carcinomas but not in adenomas. Neither ErbB2 CNG nor ErbB2 overexpression were detected in the normal controls. There was no significant association of the ErbB2 CNG with histological and clinical characteristics such as age, neutered status, histological grade, tumor size, lymph node involvement, distant metastasis, and clinical stage in the dogs with mammary carcinoma. The presence of ErbB2 CNG, but not ErbB2 overexpression, was significantly related to the shorter overall survival. These findings suggest that ErbB2 CNG is a prognostic factor in dogs with mammary carcinoma.

SUBMITTER: Sakai K

PROVIDER: S-EPMC8025436 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:For many oncogenes, increased expression resulting from copy number gain confers a selective advantage to cells that consequently make up the tumour bulk. To identify oncogenes of potential biological significance in cervical squamous cell carcinoma (SCC), 36 primary samples and ten cell lines were screened by array comparative genomic hybridization (CGH). The most commonly occurring regions of copy number gain that also showed amplification were 5p15.2–14.3 (59%), 5p13.3 (65%), and 5p13.2–13.1 (63%). Gene copy numbers were significantly associated with expression levels for three candidate oncogenes at these loci: OSMR (oncostatin M receptor) (p = 0.03), PDZK3 (PDZ domain containing protein 3) (p = 0.04), and TRIO (triple functional domain) (p = 0.03). Further examination by fluorescence in situ hybridization on a tissue microarray of 110 primary cervical SCC samples revealed copy number gain frequencies of 60.9%, 57.3%, and 54.5% for OSMR, PDZK3, and TRIO, respectively, with OSMR adversely influencing overall patient survival independently of tumour stage (p = 0.046). By array CGH, copy number gain of OSMR was not seen in any of 40 microdissected precursor cervical squamous intraepithelial lesions (SILs). Moreover, global mRNA expression analysis, using Affymetrix U133A 2.0 Arrays, showed no overexpression of OSMR in SILs, suggesting that OSMR gain and overexpression are relatively late steps in cervical carcinogenesis. In the cervical SCC cell lines CaSki and SW756, exogenous OSM activated downstream-signalling elements of OSMR including STAT3, p44/42 MAPK, and S6 ribosomal protein, and induced transcription of the angiogenic factor VEGF, effects that were reduced by OSMR depletion using RNA interference. We conclude that copy number gain of OSMR is frequently found in cervical SCC and is associated with adverse clinical outcome. As well as being a potential prognostic marker, OSMR is a candidate cell surface therapeutic target 36 primary cervical SCC samples, and 10 cervical SCC cell lines were subject to 1 Mb aCGH using a dye swapped approach. Two samples were subject to repeat. (J Pathol. 2007 Jul;212(3):325-34.)

Project description:For many oncogenes, increased expression resulting from copy number gain confers a selective advantage to cells that consequently make up the tumour bulk. To identify oncogenes of potential biological significance in cervical squamous cell carcinoma (SCC), 36 primary samples and ten cell lines were screened by array comparative genomic hybridization (CGH). The most commonly occurring regions of copy number gain that also showed amplification were 5p15.2–14.3 (59%), 5p13.3 (65%), and 5p13.2–13.1 (63%). Gene copy numbers were significantly associated with expression levels for three candidate oncogenes at these loci: OSMR (oncostatin M receptor) (p = 0.03), PDZK3 (PDZ domain containing protein 3) (p = 0.04), and TRIO (triple functional domain) (p = 0.03). Further examination by fluorescence in situ hybridization on a tissue microarray of 110 primary cervical SCC samples revealed copy number gain frequencies of 60.9%, 57.3%, and 54.5% for OSMR, PDZK3, and TRIO, respectively, with OSMR adversely influencing overall patient survival independently of tumour stage (p = 0.046). By array CGH, copy number gain of OSMR was not seen in any of 40 microdissected precursor cervical squamous intraepithelial lesions (SILs). Moreover, global mRNA expression analysis, using Affymetrix U133A 2.0 Arrays, showed no overexpression of OSMR in SILs, suggesting that OSMR gain and overexpression are relatively late steps in cervical carcinogenesis. In the cervical SCC cell lines CaSki and SW756, exogenous OSM activated downstream-signalling elements of OSMR including STAT3, p44/42 MAPK, and S6 ribosomal protein, and induced transcription of the angiogenic factor VEGF, effects that were reduced by OSMR depletion using RNA interference. We conclude that copy number gain of OSMR is frequently found in cervical SCC and is associated with adverse clinical outcome. As well as being a potential prognostic marker, OSMR is a candidate cell surface therapeutic target aCGH of high grade late stage primary cervical SCCs obtained from the archives of the Kidwai Memorial Institute of Oncology,

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ErbB2 copy number gain is associated with adverse outcome in canine mammary carcinoma.

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