The expression of the <i>neu</i> oncogene product in breast lesions and in normal fetal and adult human tissues

Potter, Christian R. De; daele, Sabine Van; Vijver, Marc J. van de; Pauwels, C; Maertens, Geert; Boever, J. De; Vandekerckhove, D; Roels, H

doi:10.1111/j.1365-2559.1989.tb01587.x

Cited by 96 publications

(41 citation statements)

References 21 publications

(5 reference statements)

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“…Furthermore, it should be acknowledged that cases of ADH as the most advanced proliferative lesion (an entity that is well characterized both morphologically and epidemiologically) are not equivalent to cases with ADH that coexists with invasive ductal carcinoma. We did not see any amplification in DH, which is consistent with results of several previous studies (11,12) and in contrast those in to other reports (15,29). In those latter reports, Her-2/neu overexpression was moderate or mild and was detected by the IHC method.…”

Section: Discussionsupporting

confidence: 93%

Amplification of Her-2/neu Gene in Her-2/neu-Overexpressing and -Nonexpressing Breast Carcinomas and Their Synchronous Benign, Premalignant, and Metastatic Lesions Detected by FISH in Archival Material

Perle

Inghirami

et al. 2002

Modern Pathology

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Amplification of Her-2/neu in breast carcinoma is associated with poor prognosis, short disease-free interval, and short survival time in both nodenegative and -positive patients. Little is known about the starting point of amplification of Her-2/ neu and how it progresses from benign to malignant breast lesions. We attempted to address these questions by evaluating amplification of Her-2/neu in benign, premalignant, and malignant lesions using fluorescence in situ hybridization (FISH). Twentysix patients with Her-2/neu-overexpressing invasive ductal carcinomas (as judged by strong immunoreactivity with Her-2/neu antibody) and coexisting lesions of ductal hyperplasia (DH), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) in the vicinity of the invasive tumor (as judged by review of the hematoxylin and eosin-stained sections), as well as metastatic carcinoma in axillary lymph nodes (mets) were selected for this study. In the primary carcinomas, a close relationship was present between overexpression as detected by immunohistochemistry (IHC) and amplification as demonstrated by FISH (85% concordance). Among these patients, amplification of Her-2/neu in ADH was demonstrated in 7 of 13 cases with ADH, and in DCIS, in 21 of 22 cases with DCIS. There was no amplification in DH or normal ductal epithelium. Significantly, in all 12 patients with synchronous positive axillary lymph nodes, there was concordant amplification of Her-2/neu in the primary and metastatic carcinoma. Amplification was consistent in multifocal metastases, despite morphological heterogeneity in some patients. Amplification ratios increased from ADH to DCIS to invasive carcinoma (P < .01, ADH versus DCIS; P < .05, DCIS versus invasive cancer), but there was no difference in amplification ratios between primary cancers and synchronous axillary metastases (P > .05). We also evaluated Her-2/neu amplification in 21 patients without Her-2/neu overexpression in their primary carcinomas (as judged by absent immunoreactivity with Her-2/neu antibody). Three showed amplification in both primary and metastatic lesions, with a low amplification ratio (approximately 2). One patient had amplification in the primary tumor but not in an axillary metastasis. Two patients exhibited slight amplification in the metastatic carcinoma (ratios 1.6 and 2), but not in their primary cancers. This FISH study indicates that amplification of Her-2/neu can emerge de novo in any stage of the disease process, from ADH to metastatic lesions, but most often appears first in ADH or DCIS. The degree of Her-2/neu amplification increases with progression to invasive carcinoma, there being no further increase in synchronous metastasis. Our data suggest that amplification of Her-2/neu appears to be mainly involved in initiation of breast oncogenesis and that its role in progression of breast cancers is uncertain. Her-2/neu, a proto-oncogene located on chromosome 17q, encodes a transmembrane tyrosine kinase with substantial homology to the epidermal growth factor receptor...

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Section: Discussionsupporting

confidence: 93%

Amplification of Her-2/neu Gene in Her-2/neu-Overexpressing and -Nonexpressing Breast Carcinomas and Their Synchronous Benign, Premalignant, and Metastatic Lesions Detected by FISH in Archival Material

Perle

Inghirami

et al. 2002

Modern Pathology

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“…A trend for an inverse correlation was found between c-erbB-2 positive tumours and the ER status. This result confirms the studies done by De Potter et al, 1989a;Thor et al, 1989;Wright et al, 1989a;Kommuss et al, 1990;De Potter et al, 1990;O'Reilly et al, 1991. It has been demonstrated that c-erbB-2 expression is under hormonal regulation (Dati et al, 1990). c-erbB-2 expression is not present in breast tissue in virgin mice and in the first 2 weeks of pregnancy when oestrogen and progesterone levels are high and maximum proliferation activity is seen.…”

Section: Discussionsupporting

confidence: 89%

c-erbB-2 positive breast tumours behave more aggressively in the first years after diagnosis

Schroeter

Potter²,

Rathsmann³

et al. 1992

Br J Cancer

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SummaryIn a retrospective study the expression of the c-erbB-2 oncogene was determined immunohistochemically in 276 breast cancer samples from 253 patients with the antibody 21N. The follow-up period was between 7 and 12 years. This study showed a trend for an inverse relationship between c-erbB-2 positive tumours and estrogen receptors (ER). A correlation was assessed between c-erbB-2 positive tumours and histological grade, liver metastases as first site of metastases, disease free survival time (DFS) in the second and third year after diagnosis and overall survival time (OST) in the third and fourth year after diagnosis. A trend was seen between c-erbB-2 positive tumours and tumour size. No correlation was found between c-erbB-2 positive tumours and age at diagnosis. The method of operation and lymph node involvement. From this study we conclude that there is a significant difference in prognosis the first years after diagnosis, but this difference seems to vanish in a longer follow-up period of 12 years. This provides us with an explanation for the discrepancies in literature concerning c-erbB-2 expression and prognosis in breast cancer. Some investigators did not show differences in prognosis between positive and negative cases after a long follow-up period whereas investigations with a short term follow-up period up to 2-3 years have indeed established a more aggressive behaviour of c-erbB-2 overexpressionary tumours.

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“…ErbB2 is rarely detected in benign lesions. [1][2][3] However, overexpression of erbB2 is frequent in DCIS and IDC. Studies of mixed lesions, containing both in situ and invasive components, invariably report that the 2 components express erbB2 coordinately.…”

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confidence: 99%

Dynamic stromal‐epithelial interactions during progression of MCF10DCIS.com xenografts

Tait

Pauley

Santner

et al. 2007

Intl Journal of Cancer

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cells form comedo type ductal carcinoma in situ in immune-deficient mice before forming invasive ductal carcinoma. As the lesions mature, both stromal and epithelial cells undergo phenotypic changes detected by immunohistochemistry. Myofibroblasts are present before the formation of carcinoma in situ and after development of invasive carcinoma. MCF10DCIS. com lesions develop a myoepithelial layer prior to exhibiting a basement membrane surrounding the ductal mass. TGFb1 is initially expressed by the epithelial cells but is expressed by stroma in invasive carcinoma. Stromal derived factor-1 is detected in epithelial cells in early carcinoma in situ but is produced in stromal cells in invasive carcinoma. The receptor CXCR4 is expressed by epithelial cells in the xenografts at all times, as is the hepatocyte growth factor receptor c-met. MCF10DCIS.com xenografts illustrate the dynamic interplay of epithelium and stroma in the development of carcinoma in situ and subsequent invasive carcinoma. Although the phenotype of the epithelial cells may be dependent upon the stroma, the malignant epithelium induces the development of the stroma necessary for progression to the invasive stage. ' 2007 Wiley-Liss, Inc.Key words: breast cancer; carcinoma in situ; MCF10DCIS.com; progression; stroma; xenograft The natural history of cancer is thought to involve multiple sequential genetic changes including mutations, loss of heterozygosity and amplification of gene copy number as well as epigenetic changes such as hypermethylation of promoter regions. In many epithelial cancers a series of abnormal histologic changes can be identified and associated with increased risk of progressing to malignant disease. It has been assumed that each stage accumulates additional genetic anomalies. The first recognized lesion with increased risk for breast cancer is hyperplasia ( a 4-fold increased risk for atypical ductal hyperplasia) but genetic anomalies are rare. ErbB2 is rarely detected in benign lesions. 1-3 However, overexpression of erbB2 is frequent in DCIS and IDC. Studies of mixed lesions, containing both in situ and invasive components, invariably report that the 2 components express erbB2 coordinately. 4-6 A similar pattern occurs for cyclin D1 expression; rare in benign hyperplastic lesions but frequent in both DCIS and IDC and expressed coordinately in both in situ and invasive components of mixed lesions. 7,8 Recent studies suggest that nearly all genetic alterations have occurred by the time of DCIS formation. Comparative genomic hybridization analysis of breast DCIS and IDC found no significant difference in the number of chromosomal abnormalities, although the frequency of a few specific changes varied in high grade versus low grade DCIS and between DCIS and concurrent IDC. 9 A more recent study confirmed that DCIS is genetically advanced. Allelic imbalance of 52 microsatellite markers of chromosomal regions commonly lost in breast cancer increased significantly between atypical ductal hyperplasia and DCIS but not between DCIS an...

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The expression of the neu oncogene product in breast lesions and in normal fetal and adult human tissues

Cited by 96 publications

References 21 publications

Amplification of Her-2/neu Gene in Her-2/neu-Overexpressing and -Nonexpressing Breast Carcinomas and Their Synchronous Benign, Premalignant, and Metastatic Lesions Detected by FISH in Archival Material

Amplification of Her-2/neu Gene in Her-2/neu-Overexpressing and -Nonexpressing Breast Carcinomas and Their Synchronous Benign, Premalignant, and Metastatic Lesions Detected by FISH in Archival Material

c-erbB-2 positive breast tumours behave more aggressively in the first years after diagnosis

Dynamic stromal‐epithelial interactions during progression of MCF10DCIS.com xenografts

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