title: A positive role for PEA3 in HER2-mediated breast tumour progression.
abstract: Overexpression of HER2 is associated with an adverse prognosis in breast cancer. Despite this, the mechanism of its transcriptional regulation remains poorly understood. PEA3, a MAP kinase (MAPK)-activated member of the Ets transcription factor family has been implicated in the transcriptional regulation of HER2. The direction of its modulation remains controversial. We assessed relative levels of PEA3 expression and DNA binding in primary breast cultures derived from patient tumours (n=18) in the presence of an activated MAPK pathway using Western blotting and shift analysis. Expression of PEA3 in breast tumours from patients of known HER2 status (n=107) was examined by immunohistochemistry. In primary breast cancer cell cultures, growth factors induced interaction between PEA3 and its DNA response element. Upregulation of PEA3 expression in the presence of growth factors associated with HER2 positivity and axillary lymph node metastasis (P=0.034 and 0.049, respectively). PEA3 expression in breast cancer tissue associated with reduced disease-free survival (P<0.001), Grade III tumours (P<0.0001) and axillary lymph node metastasis (P=0.026). Co-expression of PEA3 and HER2 significantly associated with rate of recurrence compared to patients who expressed HER2 alone (P=0.0039). These data support a positive role for PEA3 in HER2-mediated oncogenesis in breast cancer.
authors.affiliation: School of Medicine and Medical Science, Saint Vincent's University Hospital, Dublin, Ireland.
authors.forename: E
authors.initials: E
authors.lastname: Myers
authors.forename: A D K
authors.initials: AD
authors.lastname: Hill
authors.forename: G
authors.initials: G
authors.lastname: Kelly
authors.forename: E W
authors.initials: EW
authors.lastname: McDermott
authors.forename: N J
authors.initials: NJ
authors.lastname: O'Higgins
authors.forename: L S
authors.initials: LS
authors.lastname: Young
mesh_terms: D001365:Axilla / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D024202:Electrophoretic Mobility Shift Assay; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis / Q000473:pathology; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015996:Survival Rate; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000187:drug effects; D048490:raf Kinases / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D004815:Epidermal Growth Factor; D016222:Fibroblast Growth Factor 2; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D048490:raf Kinases; C065788:transcription factor PEA3