Role of δ16HER2 splice variant in breast tumor progression and response to HER2-targeted therapy

Serenella M. Pupa, Manuela Campiglio, Anna Rossini, Rosaria Orlandi, Valentina Ciravolo, Augusto Amici, Elda Tagliabue

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

HER2 overexpression is necessary but not sufficient to induce malignant transformation, as clearly shown in mice transgenically expressing the rat protooncogene HER2/neu but only developing tumors when accompanied by alterations such as deletions in the HER2 extracellular domain. Interestingly, an alternative splice form of the human homologous HER2 gene with an in-frame deletion in the same region mutated in neu protooncogene transgenic mice has been detected in human breast carcinomas. This splice variant encodes a receptor lacking exon 16, which immediately precedes the transmembrane domain containing two cysteine residues. Loss of these cysteine residues causes a conformational change in the HER2 receptor extracellular domain that favors intermolecular disulfide bonding and, consequently, homodimerization leading to cell transformation. Real-time PCR analysis revealed that the Δ16HER2 variant represents about 9% of the HER2 transcripts in human primary breast tumors. Athymic mice develop mammary tumors after injection of cells ectopically expressing the Δ16HER2 variant, which forms stable dimers and couples to multiple oncogenic signaling through activated Src kinase pathways. Thus, the Δ16HER2 isoform appears to be one, if not the only, oncogenic variant of the human HER2 proto-oncogene. Furthermore, Δ16HER2 compromises trastuzumab action, strongly suggesting that trastuzumab-non-responsive patients express high levels of stable Δ16HER2 dimers on their HER2-amplified/overexpressed tumors that to some extent impair drug binding and therapeutic benefits. Such a hypothesis is consistent with clinical studies showing that increased HER2 FISH ratios (>8) decrease susceptibility to trastuzumab.

Original languageEnglish
Title of host publicationHER2 and Cancer: Mechanism, Testing and Targeted Therapy
PublisherNova Science Publishers, Inc.
Pages201-209
Number of pages9
ISBN (Print)9781611226508
Publication statusPublished - Feb 2011

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Tumors
Breast Neoplasms
Dimers
Cysteine
erbB-2 Genes
Proto-Oncogenes
src-Family Kinases
Therapeutics
Nude Mice
Disulfides
Transgenic Mice
Rats
Real-Time Polymerase Chain Reaction
Exons
Neoplasms
Protein Isoforms
Genes
Injections
Pharmaceutical Preparations
Trastuzumab

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Pupa, S. M., Campiglio, M., Rossini, A., Orlandi, R., Ciravolo, V., Amici, A., & Tagliabue, E. (2011). Role of δ16HER2 splice variant in breast tumor progression and response to HER2-targeted therapy. In HER2 and Cancer: Mechanism, Testing and Targeted Therapy (pp. 201-209). Nova Science Publishers, Inc..

Role of δ16HER2 splice variant in breast tumor progression and response to HER2-targeted therapy. / Pupa, Serenella M.; Campiglio, Manuela; Rossini, Anna; Orlandi, Rosaria; Ciravolo, Valentina; Amici, Augusto; Tagliabue, Elda.

HER2 and Cancer: Mechanism, Testing and Targeted Therapy. Nova Science Publishers, Inc., 2011. p. 201-209.

Research output: Chapter in Book/Report/Conference proceedingChapter

Pupa, SM, Campiglio, M, Rossini, A, Orlandi, R, Ciravolo, V, Amici, A & Tagliabue, E 2011, Role of δ16HER2 splice variant in breast tumor progression and response to HER2-targeted therapy. in HER2 and Cancer: Mechanism, Testing and Targeted Therapy. Nova Science Publishers, Inc., pp. 201-209.
Pupa SM, Campiglio M, Rossini A, Orlandi R, Ciravolo V, Amici A et al. Role of δ16HER2 splice variant in breast tumor progression and response to HER2-targeted therapy. In HER2 and Cancer: Mechanism, Testing and Targeted Therapy. Nova Science Publishers, Inc. 2011. p. 201-209
Pupa, Serenella M. ; Campiglio, Manuela ; Rossini, Anna ; Orlandi, Rosaria ; Ciravolo, Valentina ; Amici, Augusto ; Tagliabue, Elda. / Role of δ16HER2 splice variant in breast tumor progression and response to HER2-targeted therapy. HER2 and Cancer: Mechanism, Testing and Targeted Therapy. Nova Science Publishers, Inc., 2011. pp. 201-209
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