title: 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.
authors.affiliation: Institute of Pathology, Medical Faculty of the University of Bonn, D-53127 Bonn, Germany. susanne.haas@ukb.uni-bonn.de
authors.forename: Susanne
authors.initials: S
authors.lastname: Haas
authors.forename: Heidrun
authors.initials: H
authors.lastname: Gevensleben
authors.forename: Sylvia
authors.initials: S
authors.lastname: Rabstein
authors.forename: Volker
authors.initials: V
authors.lastname: Harth
authors.forename: Beate
authors.initials: B
authors.lastname: Pesch
authors.forename: Thomas
authors.initials: T
authors.lastname: Brüning
authors.forename: Christina
authors.initials: C
authors.lastname: Justenhoven
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.forename: Yon-Dschun
authors.initials: YD
authors.lastname: Ko
authors.forename: Christian
authors.initials: C
authors.lastname: Baisch
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Fischer
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D066246:ErbB Receptors / Q000096:biosynthesis*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009367:Neoplasm Staging; D020890:Neuregulin-1 / Q000096:biosynthesis*; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D020893:Receptor, ErbB-3 / Q000096:biosynthesis*; D066247:Receptor, ErbB-4; D015533:Transcriptional Activation
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C587689:ERBB4 protein, human