title: PDK1 promotes tumor growth and metastasis in a spontaneous breast cancer model.
abstract: Because malignant cells have altered, usually accelerated, energy consumption, targeting metabolic signaling represents a prevailing strategy for tumor therapy. Phosphoinositide-dependent kinase 1 (PDK1) is a proximal signaling molecule of phosphatidylinositol 3-kinase, which is required for metabolic activation. It is still lacking definitive evidence whether inactivation of PDK1 can overwhelm tumorigenesis in vivo. Herein we revealed that mammary-specific ablation of PDK1 could delay tumor initiation, progression and metastasis in a spontaneous mouse tumor model. We also demonstrated that inducible deletion of PDK1 could noticeably shrink the growing breast tumors. However, a small portion of PDK1-deficient tumorigenic cells eventually established tumor lesions, albeit at a relatively later phase, most likely owing to compensatory upregulation of extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation. Consequently, simultaneous inhibition of PDK1 and Erk1/2 impeded the survival of breast cancer cells. Thus we identify PDK1 as a potential therapeutic target for breast cancer, particularly in combination with an Erk1/2 inhibitor.
authors.affiliation: School of Medicine, Tsinghua University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Du
authors.affiliation: School of Medicine, Tsinghua University, Beijing, China.
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.affiliation: School of Medicine, Tsinghua University, Beijing, China.|Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.affiliation: School of Medicine, Tsinghua University, Beijing, China.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: Center of Animal Facility, Tsinghua University, Beijing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Chang
authors.affiliation: School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases