title: Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas.
abstract: Loss of the tumor suppressor gene PTEN is implicated in breast cancer progression and resistance to targeted therapies, and is thought to promote tumorigenesis by activating PI3K signaling. In a transgenic model of breast cancer, Pten suppression using a tetracycline-regulatable short hairpin (sh)RNA cooperates with human epidermal growth factor receptor 2 (HER2/neu), leading to aggressive and metastatic disease with elevated signaling through PI3K and, surprisingly, the mitogen-activated protein kinase (MAPK) pathway. Restoring Pten function is sufficient to down-regulate both PI3K and MAPK signaling and triggers dramatic tumor regression. Pharmacologic inhibition of MAPK signaling produces similar effects to Pten restoration, suggesting that the MAPK pathway contributes to the maintenance of advanced breast cancers harboring Pten loss.
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
authors.forename: Saya H
authors.initials: SH
authors.lastname: Ebbesen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
authors.forename: Carl U
authors.initials: CU
authors.lastname: Bialucha
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
authors.forename: Natasha
authors.initials: N
authors.lastname: Morse
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
authors.forename: Edward R
authors.initials: ER
authors.lastname: Kastenhuber
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
authors.forename: Hannah Y
authors.initials: HY
authors.lastname: Wen
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
authors.forename: Lukas E
authors.initials: LE
authors.lastname: Dow
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065; Department of Medicine, Weill Cornell Medicine, New York, NY 10065;
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; Howard Hughes Medical Institute, New York, NY 10065 lowes@mskcc.org.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000172:deficiency / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D009363:Neoplasm Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C514862:Akt1 protein, mouse; C482125:MAP2K1 protein, human; C487757:Pten protein, mouse
keywords: RNAi; breast cancer; mouse models; targeted therapies; tumor suppressors