Her2/neu extracellular domain shedding in uterine serous carcinoma: implications for immunotherapy with trastuzumab View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2011-10

AUTHORS

P Todeschini, E Cocco, S Bellone, J Varughese, K Lin, L Carrara, F Guzzo, N Buza, P Hui, D-A Silasi, E Ratner, M Azodi, P E Schwartz, T J Rutherford, S Pecorelli, A D Santin

ABSTRACT

BACKGROUND: We evaluated shedding of epidermal growth factor type II receptor (Her2/neu) extracellular domain (ECD) in primary uterine serous carcinoma (USC) cell lines and in the serum of USC patients and its biological effects in experiments of trastuzumab-induced cytotoxicity in vitro. METHODS: Her2/neu expression was evaluated by immunohistochemistry (IHC), real-time PCR and flow cytometry, while c-erbB2 gene amplification was assessed using fluorescent in situ hybridisation (FISH). Her2/neu ECD levels in the supernatants of USC cell lines and in the serum of 38 USC patients and 19 controls were tested using ELISA. The biologic effect of Her2/neu ECD on trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated in 5-h chromium-release assays. RESULTS: Five out of ten USC cell lines overexpressed Her2/neu by IHC and showed amplification of the c-erbB2 gene. High levels of Her2/neu ECD were found in supernatants of all FISH-positive tumours. In contrast, FISH-negative USC was negative for Her2/neu ECD shedding. Serum Her2/neu ECD levels in patients harbouring 3+Her2/neu tumours were higher than those found in healthy women (P=0.02) or USC patients with 2+ or 1+/negative Her2/neu expression (P=0.02). In cytotoxicity experiments, trastuzumab-mediated ADCC was significantly decreased by the addition of Her2/neu ECD-containing supernatants (P=0.01). CONCLUSION: FISH-positive c-erbB2 USC cell lines shed high levels of Her2/neu ECD. High levels of Her2/neu ECD in USC patients may reduce trastuzumab-mediated ADCC in vitro and potentially neutralise its therapeutic effect in vivo. More... »

PAGES

1176

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/bjc.2011.369

DOI

http://dx.doi.org/10.1038/bjc.2011.369

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1003179963

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/21915118


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