title: The ErbB2ΔEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment.
abstract: Amplification and overexpression of erbB2/neu proto-oncogene is observed in 20-30% human breast cancer and is inversely correlated with the survival of the patient. Despite this, somatic activating mutations within erbB2 in human breast cancers are rare. However, we have previously reported that a splice isoform of erbB2, containing an in-frame deletion of exon 16 (herein referred to as ErbB2ΔEx16), results in oncogenic activation of erbB2 because of constitutive dimerization of the ErbB2 receptor. Here, we demonstrate that the ErbB2ΔEx16 is a major oncogenic driver in breast cancer that constitutively signals from the cell surface. We further show that inducible expression of the ErbB2ΔEx16 variant in mammary gland of transgenic mice results in the rapid development of metastatic multifocal mammary tumors. Genetic and biochemical characterization of the ErbB2ΔEx16-derived mammary tumors exhibit several unique features that distinguish this model from the conventional ErbB2 ones expressing the erbB2 proto-oncogene in mammary epithelium. Unlike the wild-type ErbB2-derived tumors that express luminal keratins, ErbB2ΔEx16-derived tumors exhibit high degree of intratumoral heterogeneity co-expressing both basal and luminal keratins. Consistent with these distinct pathological features, the ErbB2ΔEx16 tumors exhibit distinct signaling and gene expression profiles that correlate with activation of number of key transcription factors implicated in breast cancer metastasis and cancer stem cell renewal.
authors.affiliation: Goodman Cancer Center, Montreal, Quebec, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Turpin
authors.affiliation: Goodman Cancer Center, Montreal, Quebec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Ling
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Crosby
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, USA.
authors.forename: Z C
authors.initials: ZC
authors.lastname: Hartman
authors.affiliation: Goodman Cancer Center, Montreal, Quebec, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Simond
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Chodosh
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Rennhack
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Andrechek
authors.affiliation: Goodman Cancer Center, Montreal, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Ozcelik
authors.affiliation: Goodman Cancer Center, Montreal, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Hallett
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, Houston TX, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Pathology, Center for Comparative Medicine, University of California Davis, Davis, CA, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Cardiff
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Gray
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: O L
authors.initials: OL
authors.lastname: Griffith
authors.affiliation: Goodman Cancer Center, Montreal, Quebec, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada.|Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: W J
authors.initials: WJ
authors.lastname: Muller
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005091:Exons; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D010641:Phenotype; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D017384:Sequence Deletion; D014157:Transcription Factors / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; C000715470:MAS1 protein, human