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Expression of heregulin, phosphorylated HER-2, HER-3 and HER-4 in HER-2 negative breast cancers.

Abstract
A significant number of HER-2 amplified breast cancers is effectively treated by trastuzumab and further shows receptor-enhanced chemosensitivity. Recent studies have postulated transactivation of HER-2 also in tumors expressing phosphorylated/activated HER-2 (pHER-2) and of the HER-3/HER-4 ligand heregulin (HRG), independent of HER-2 amplification. As a consequence, a subset of tumors without HER-2 overexpression would be sensitive to trastuzumab chemotherapy. To investigate the potential transactivation of HER-2, in 171 breast cancers from the GENICA study with negative/low expression of HER-2 we analyzed the expression of pHER-2, HRG, HER-3 and HER-4 by immunohistochemistry. None of the tumors examined displayed expression of pHER-2. Moderate or strong cytoplasmic staining of HRG, HER-3 and HER-4 was observed in 44 (26%), 67 (39%) and 33 (19%) cases, respectively. No association of HRG, HER-3 and HER-4 with the survival of patients or with known prognostic clinical factors was seen. In conclusion, our data obtained on a well-characterized cohort of breast cancers provide no evidence of HER-2-activation in the absence of HER-2 overexpression. The biological function and clinical implications of HRG, HER-3 and HER-4 in this group of tumors remain unclear. Our results cannot support the hypothesis of a transactivation of HER-2 and thus a possible therapeutic benefit of trastuzumab in HER-2 negative breast cancers.
AuthorsSusanne Haas, Heidrun Gevensleben, Sylvia Rabstein, Volker Harth, Beate Pesch, Thomas Brüning, Christina Justenhoven, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, Christian Baisch, Hans-Peter Fischer, Reinhard Büttner
JournalOncology reports (Oncol Rep) Vol. 21 Issue 2 Pg. 299-304 (Feb 2009) ISSN: 1021-335X [Print] Greece
PMID19148499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Biomarkers, Tumor
  • Neuregulin-1
  • ERBB4 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Receptor, ErbB-4
Topics
  • Adult
  • Aged
  • Biomarkers, Tumor (analysis)
  • Breast Neoplasms (metabolism, pathology)
  • Case-Control Studies
  • ErbB Receptors (biosynthesis)
  • Female
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Middle Aged
  • Neoplasm Staging
  • Neuregulin-1 (biosynthesis)
  • Phosphorylation
  • Receptor, ErbB-2 (biosynthesis)
  • Receptor, ErbB-3 (biosynthesis)
  • Receptor, ErbB-4
  • Transcriptional Activation

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