Tyrosine kinase activation in breast carcinoma with correlation to HER-2/neu gene amplification and receptor overexpression

Rohit Bhargava, Rizwan C. Naeem, Sharon Marconi, Jason Luszcz, Jane Garb, Robert Gasparini, Christopher N. Otis

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The HER-2/neu oncogene encodes a transmembrane receptor with intrinsic tyrosine kinase activity. A pilot study was performed to investigate downstream effects of HER-2/neu (or related growth factor receptor) activation by identifying phosphorylated tyrosine. Fifty-four breast carcinomas were evaluated for HER-2/neu overexpression by the HercepTest (Dako, Carpinteria, CA) and the monoclonal CB11 antibody (Ventana, Tucson, AZ). Phosphotyrosine (an indication of tyrosine kinase activity) was detected by an antiphosphotyrosine mouse monoclonal antibody (Upstate Biotechnology, Lake Placid, NY). The gene amplification status was evaluated in 50 of the 54 cases by fluorescence in situ hybridization (FISH) using the Ventana gene probe. The HER-2/neu oncogene amplification was detected in 28% (14 of 50) of cases. Of the 14 cases showing oncogene amplification, tyrosine kinase activity was detected in 9 (64.2%) cases. There was moderate agreement between HER-2/neu gene amplification and tyrosine kinase activity (κ = 0.43). Immunohistochemical staining of 3+ (with both HercepTest and CB11) showed better agreement with HER-2/neu oncogene amplification and increased tyrosine kinase activity than 2+ immunohistochemical staining. Overall, oncogene amplification and overexpression correlated with increased tyrosine kinase activity, supporting the mechanism of tyrosine kinase activation by HER-2/neu amplification and overexpression. However, 7 cases showing increased tyrosine kinase activity did not show gene amplification or 3+ receptor expression (by either HercepTest or CB11), raising the possibility of other growth factor receptors operating via the tyrosine kinase pathway. There was no apparent correlation between tyrosine kinase activity and hormone receptor status (estrogen or progesterone). Increased tyrosine kinase activity is more commonly associated with higher-grade tumors and thus may correlate with aggressive biologic behavior in breast carcinoma. The results of this pilot study suggest that a larger-scale investigation into downstream activation of tyrosine kinase and correlation to clinical outcome or response to Herceptin therapy may identify subsets of patients whose clinical response or outcome may be predicted by tyrosine kinase activation.

Original languageEnglish (US)
Pages (from-to)1344-1350
Number of pages7
JournalHuman Pathology
Volume32
Issue number12
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

ErbB-2 Receptor
erbB-2 Genes
Gene Amplification
Protein-Tyrosine Kinases
Breast Neoplasms
Oncogenes
Growth Factor Receptors
TYK2 Kinase
Monoclonal Antibodies
Staining and Labeling
Phosphotyrosine
Progesterone Receptors
Biotechnology
Lakes
Fluorescence In Situ Hybridization
Estrogen Receptors
Tyrosine

Keywords

  • Breast carcinoma
  • HER-2/neu
  • Tyrosine kinase

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Tyrosine kinase activation in breast carcinoma with correlation to HER-2/neu gene amplification and receptor overexpression. / Bhargava, Rohit; Naeem, Rizwan C.; Marconi, Sharon; Luszcz, Jason; Garb, Jane; Gasparini, Robert; Otis, Christopher N.

In: Human Pathology, Vol. 32, No. 12, 2001, p. 1344-1350.

Research output: Contribution to journalArticle

Bhargava, Rohit ; Naeem, Rizwan C. ; Marconi, Sharon ; Luszcz, Jason ; Garb, Jane ; Gasparini, Robert ; Otis, Christopher N. / Tyrosine kinase activation in breast carcinoma with correlation to HER-2/neu gene amplification and receptor overexpression. In: Human Pathology. 2001 ; Vol. 32, No. 12. pp. 1344-1350.
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AU - Naeem, Rizwan C.

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AU - Luszcz, Jason

AU - Garb, Jane

AU - Gasparini, Robert

AU - Otis, Christopher N.

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AB - The HER-2/neu oncogene encodes a transmembrane receptor with intrinsic tyrosine kinase activity. A pilot study was performed to investigate downstream effects of HER-2/neu (or related growth factor receptor) activation by identifying phosphorylated tyrosine. Fifty-four breast carcinomas were evaluated for HER-2/neu overexpression by the HercepTest (Dako, Carpinteria, CA) and the monoclonal CB11 antibody (Ventana, Tucson, AZ). Phosphotyrosine (an indication of tyrosine kinase activity) was detected by an antiphosphotyrosine mouse monoclonal antibody (Upstate Biotechnology, Lake Placid, NY). The gene amplification status was evaluated in 50 of the 54 cases by fluorescence in situ hybridization (FISH) using the Ventana gene probe. The HER-2/neu oncogene amplification was detected in 28% (14 of 50) of cases. Of the 14 cases showing oncogene amplification, tyrosine kinase activity was detected in 9 (64.2%) cases. There was moderate agreement between HER-2/neu gene amplification and tyrosine kinase activity (κ = 0.43). Immunohistochemical staining of 3+ (with both HercepTest and CB11) showed better agreement with HER-2/neu oncogene amplification and increased tyrosine kinase activity than 2+ immunohistochemical staining. Overall, oncogene amplification and overexpression correlated with increased tyrosine kinase activity, supporting the mechanism of tyrosine kinase activation by HER-2/neu amplification and overexpression. However, 7 cases showing increased tyrosine kinase activity did not show gene amplification or 3+ receptor expression (by either HercepTest or CB11), raising the possibility of other growth factor receptors operating via the tyrosine kinase pathway. There was no apparent correlation between tyrosine kinase activity and hormone receptor status (estrogen or progesterone). Increased tyrosine kinase activity is more commonly associated with higher-grade tumors and thus may correlate with aggressive biologic behavior in breast carcinoma. The results of this pilot study suggest that a larger-scale investigation into downstream activation of tyrosine kinase and correlation to clinical outcome or response to Herceptin therapy may identify subsets of patients whose clinical response or outcome may be predicted by tyrosine kinase activation.

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