title: Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers.
abstract: While estrogens have been shown to modulate EGFR/HER-1 and HER-2/neu expression in experimental systems, the effects of estrogen deprivation on expression levels of the HER-receptors and the neuregulin (NRG)1 ligand in breast cancers remain unknown. Here, we measured EGFR/HER-1-4 and NRG1 mRNA in ER positive tumors from 85 postmenopausal breast cancer patients before and after two weeks (n=64) and three months (n=85) of primary treatment with an aromatase inhibitor (AI). In tumors lacking HER-2/neu amplification, quantitative real-time PCR analyses revealed EGFR/HER-1 and NRG1 to vary significantly between the three time points (before therapy, after 2 weeks and after 3 months on treatment; P≤0.001 for both). Pair-wise comparison revealed a significant increase in EGFR/HER-1 already during the first two weeks of treatment (P=0.049) with a further increase for both EGFR/HER-1 and NRG1 after 3 months on treatment (P≤0.001 and P=0.001 for both comparing values at 3 months to values at baseline and 2 weeks respectively). No difference between tumors responding versus non-responders was recorded. Further, no significant change in any parameter was observed among HER-2/neu amplified tumors. Analyzing components of the HER-2/neu PI3K/Akt downstream pathway, the PIK3CA H1047R mutation was associated with treatment response (P=0.035); however no association between either AKT phosphorylation status or PIK3CA gene mutations and EGFR/HER-1 or NRG1 expression levels were observed. Our results indicate primary AI treatment to modulate expression of HER-family members and the growth factor NRG1 in HER-2/neu non-amplified breast cancers in vivo. Potential implications to long term sensitivity warrants further investigations.
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Hormone Laboratory, Haukeland University Hospital, 5021 Bergen, Norway. Electronic address: Marianne.flageng@uib.no.
authors.forename: Marianne Hauglid
authors.initials: MH
authors.lastname: Flågeng
authors.affiliation: University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom; Department of Medical Genetics, Cambridge University, Cambridge, United Kingdom. Electronic address: alexey_larionov@hotmail.com.
authors.forename: Alexey
authors.initials: A
authors.lastname: Larionov
authors.affiliation: Department of Oncology, Akershus University Hospital, 1478 Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, 0316 Oslo, Norway. Electronic address: juergen.geisler@medisin.uio.no.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Geisler
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway. Electronic address: stian.knappskog@uib.no.
authors.forename: Stian
authors.initials: S
authors.lastname: Knappskog
authors.affiliation: Department of Technology, University College of Sør-Trøndelag, 7491 Trondheim, Norway. Electronic address: wenche.s.prestvik@hist.no.
authors.forename: Wenche S
authors.initials: WS
authors.lastname: Prestvik
authors.affiliation: Department of Technology, University College of Sør-Trøndelag, 7491 Trondheim, Norway. Electronic address: geir.bjorkoy@hist.no.
authors.forename: Geir
authors.initials: G
authors.lastname: Bjørkøy
authors.affiliation: The Gades Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway; Department of Pathology, Haukeland University Hospital, 5021 Bergen, Norway. Electronic address: peer.kare.lilleng@helse-bergen.no.
authors.forename: Peer Kåre
authors.initials: PK
authors.lastname: Lilleng
authors.affiliation: University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. Electronic address: Mike.Dixon@ed.ac.uk.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Dixon
authors.affiliation: University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. Electronic address: w.r.miller@ed.ac.uk.
authors.forename: William R
authors.initials: WR
authors.lastname: Miller
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway. Electronic address: Marianne.flageng@uib.no.
authors.forename: Per Eystein
authors.initials: PE
authors.lastname: Lønning
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Hormone Laboratory, Haukeland University Hospital, 5021 Bergen, Norway. Electronic address: Marianne.flageng@uib.no.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Mellgren
mesh_terms: D000077384:Anastrozole; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D000077289:Letrozole; D009154:Mutation; D020890:Neuregulin-1 / Q000378:metabolism*; D009570:Nitriles / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use
chemical_list: D000077384:Anastrozole; D047072:Aromatase Inhibitors; D066246:ErbB Receptors; D047628:Estrogen Receptor alpha; D000077289:Letrozole; D020890:Neuregulin-1; D009570:Nitriles; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D014230:Triazoles; C506487:ESR1 protein, human; C094131:NRG1 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: Breast cancer; Endocrine therapy; ErbB; Neuregulin-1