title: PTPN12 promotes resistance to oxidative stress and supports tumorigenesis by regulating FOXO signaling.
abstract: It is well known that protein tyrosine phosphatases (PTPs) that become oxidized due to exposure to reactive oxygen species (ROS) undergo a conformational change and are inactivated. However, whether PTPs can actively regulate ROS levels in order to prevent PTP inhibition has yet to be investigated. Here, we demonstrate that PTP non-receptor type 12 (PTPN12) protects cells against aberrant ROS accumulation and death induced by oxidative stress. Murine embryonic fibroblasts (MEFs) deficient in PTPN12 underwent increased ROS-induced apoptosis under conditions of antioxidant depletion. Cells lacking PTPN12 also showed defective activation of FOXO1/3a, transcription factors required for the upregulation of several antioxidant genes. PTPN12-mediated regulation of ROS appeared to be mediated by phosphoinositide-dependent kinase-1 (PDK1), which was hyperstimulated in the absence of PTPN12. As tight regulation of ROS to sustain survival is a key feature of cancer cells, we examined PTPN12 levels in tumors from a cohort of breast cancer patients. Patients whose tumors showed high levels of PTPN12 transcripts had a significantly poorer prognosis. Analysis of tissues from patients with various breast cancer subtypes revealed that more triple-negative breast cancers, the most aggressive breast cancer subtype, showed high PTPN12 expression than any other subtype. Furthermore, both human breast cancer cells and mouse mammary epithelial tumor cells engineered to lack PTPN12 exhibited reduced tumorigenic and metastatic potential in vivo that correlated with their elevated ROS levels. The involvement of PTPN12 in the antioxidant response of breast cancer cells suggests that PTPN12 may represent a novel therapeutic target for this disease.
authors: 1] The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: I S
authors: IS
authors: Harris
authors: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
authors: H
authors: H
authors: Blaser
authors: 1] The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada [2] Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada [3] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors: J
authors: J
authors: Moreno
authors: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
authors: A E
authors: AE
authors: Treloar
authors: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
authors: C
authors: C
authors: Gorrini
authors: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
authors: M
authors: M
authors: Sasaki
authors: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
authors: J M
authors: JM
authors: Mason
authors: 1] The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada [2] Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
authors: C B
authors: CB
authors: Knobbe
authors: Laboratory of Apoptosis in Cancer, MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors: A
authors: A
authors: Rufini
authors: Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada.
authors: M
authors: M
authors: Hallé
authors: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
authors: A J
authors: AJ
authors: Elia
authors: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
authors: A
authors: A
authors: Wakeham
authors: Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada.
authors: M L
authors: ML
authors: Tremblay
authors: Laboratory of Apoptosis in Cancer, MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors: G
authors: G
authors: Melino
authors: 1] The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada [3] Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada [4] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors: S
authors: S
authors: Done
authors: 1] The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: T W
authors: TW
authors: Mak
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002455:Cell Division; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018384:Oxidative Stress; D011379:Prognosis; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C516738:PTPN12 protein, human; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12