title: Modeling invasive breast cancer: growth factors propel progression of HER2-positive premalignant lesions.
abstract: The HER2/neu oncogene encodes a receptor-like tyrosine kinase whose overexpression in breast cancer predicts poor prognosis and resistance to conventional therapies. However, the mechanisms underlying aggressiveness of HER2 (human epidermal growth factor receptor 2)-overexpressing tumors remain incompletely understood. Because it assists epidermal growth factor (EGF) and neuregulin receptors, we overexpressed HER2 in MCF10A mammary cells and applied growth factors. HER2-overexpressing cells grown in extracellular matrix formed filled spheroids, which protruded outgrowths upon growth factor stimulation. Our transcriptome analyses imply a two-hit model for invasive growth: HER2-induced proliferation and evasion from anoikis generate filled structures, which are morphologically and transcriptionally analogous to preinvasive patients' lesions. In the second hit, EGF escalates signaling and transcriptional responses leading to invasive growth. Consistent with clinical relevance, a gene expression signature based on the HER2/EGF-activated transcriptional program can predict poorer prognosis of a subgroup of HER2-overexpressing patients. In conclusion, the integration of a three-dimensional cellular model and clinical data attributes progression of HER2-overexpressing lesions to EGF-like growth factors acting in the context of the tumor's microenvironment.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: C-R
authors.initials: CR
authors.lastname: Pradeep
authors.forename: A
authors.initials: A
authors.lastname: Zeisel
authors.forename: W J
authors.initials: WJ
authors.lastname: Köstler
authors.forename: M
authors.initials: M
authors.lastname: Lauriola
authors.forename: J
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: B
authors.initials: B
authors.lastname: Haibe-Kains
authors.forename: N
authors.initials: N
authors.lastname: Amariglio
authors.forename: N
authors.initials: N
authors.lastname: Ben-Chetrit
authors.forename: A
authors.initials: A
authors.lastname: Emde
authors.forename: I
authors.initials: I
authors.lastname: Solomonov
authors.forename: G
authors.initials: G
authors.lastname: Neufeld
authors.forename: M
authors.initials: M
authors.lastname: Piccart
authors.forename: I
authors.initials: I
authors.lastname: Sagi
authors.forename: C
authors.initials: C
authors.lastname: Sotiriou
authors.forename: G
authors.initials: G
authors.lastname: Rechavi
authors.forename: E
authors.initials: E
authors.lastname: Domany
authors.forename: C
authors.initials: C
authors.lastname: Desmedt
authors.forename: Y
authors.initials: Y
authors.lastname: Yarden
mesh_terms: D023102:Anoikis / Q000502:physiology; D001943:Breast Neoplasms / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D011230:Precancerous Conditions / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D018874:Spheroids, Cellular / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human