title: ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis.
abstract: The ErbB receptor family member ErbB3 has been implicated in breast cancer growth, but it has yet to be determined whether its disruption is therapeutically valuable. In a mouse model of mammary carcinoma driven by the polyomavirus middle T (PyVmT) oncogene, the ErbB2 tyrosine kinase inhibitor lapatinib reduced the activation of ErbB3 and Akt as well as tumor cell growth. In this phosphatidylinositol-3 kinase (PI3K)-dependent tumor model, ErbB2 is part of a complex containing PyVmT, p85 (PI3K), and ErbB3, that is disrupted by treatment with lapatinib. Thus, full engagement of PI3K/Akt by ErbB2 in this oncogene-induced mouse tumor model may involve its ability to dimerize with and phosphorylate ErbB3, which itself directly binds PI3K. In this article, we report that ErbB3 is critical for PI3K/Akt-driven tumor formation triggered by the PyVmT oncogene. Tissue-specific, Cre-mediated deletion of ErbB3 reduced Akt phosphorylation, primary tumor growth, and pulmonary metastasis. Furthermore, EZN-3920, a chemically stabilized antisense oligonucleotide that targets the ErbB3 mRNA in vivo, produced similar effects while causing no toxicity in the mouse model. Our findings offer further preclinical evidence that ErbB3 ablation may be therapeutically effective in tumors where ErbB3 engages PI3K/Akt signaling.
authors.affiliation: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
authors.forename: Joan T
authors.initials: JT
authors.lastname: Garrett
authors.forename: Violeta
authors.initials: V
authors.lastname: Sánchez
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Stanford
authors.forename: Christian
authors.initials: C
authors.lastname: Young
authors.forename: Anindita
authors.initials: A
authors.lastname: Chakrabarty
authors.forename: Cammie
authors.initials: C
authors.lastname: Rinehart
authors.forename: Yixian
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yaming
authors.initials: Y
authors.lastname: Wu
authors.forename: Lee
authors.initials: L
authors.lastname: Greenberger
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Horak
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000201:enzymology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008822:Mice, Transgenic; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016376:Oligonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases; D020893:Receptor, ErbB-3; D051057:Proto-Oncogene Proteins c-akt