title: MITF depletion elevates expression levels of ERBB3 receptor and its cognate ligand NRG1-beta in melanoma.
abstract: The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway is frequently hyper-activated upon vemurafenib treatment of melanoma. We have here investigated the relationship between SRY-box 10 (SOX10), forkhead box 3 (FOXD3) and microphthalmia-associated transcription factor (MITF) in the regulation of the receptor tyrosine-protein kinase ERBB3, and its cognate ligand neuregulin 1-beta (NRG1-beta). We found that both NRG1-beta and ERBB3 mRNA levels were elevated as a consequence of MITF depletion, induced by either vemurafenib or MITF small interfering RNA (siRNA) treatment. Elevation of ERBB3 receptor expression after MITF depletion caused increased activation of the PI3K pathway in the presence of NRG1-beta ligand. Together, our results suggest that MITF may play a role in the development of acquired drug resistance through hyper-activation of the PI3K pathway.
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Tine N
authors.initials: TN
authors.lastname: Alver
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Lavelle
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Ane S
authors.initials: AS
authors.lastname: Longva
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Geir F
authors.initials: GF
authors.lastname: Øy
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.|Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Department of Informatics, University of Oslo, Oslo, Norway.
authors.forename: Eivind
authors.initials: E
authors.lastname: Hovig
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Sigurd L
authors.initials: SL
authors.lastname: Bøe
mesh_terms: D045744:Cell Line, Tumor; D051858:Forkhead Transcription Factors / Q000032:analysis; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000032:analysis / Q000502:physiology*; D020890:Neuregulin-1 / Q000032:analysis*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000032:analysis*; D055757:SOXE Transcription Factors / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: C503514:FOXD3 protein, human; D051858:Forkhead Transcription Factors; D007211:Indoles; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C094131:NRG1 protein, human; D020890:Neuregulin-1; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; D013449:Sulfonamides; D000077484:Vemurafenib; D019869:Phosphatidylinositol 3-Kinases; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; D051057:Proto-Oncogene Proteins c-akt
keywords: ERBB3; MITF; NRG1-beta; PI3K signaling; melanoma