title: Role of Runx2 in IGF-1Rβ/Akt- and AMPK/Erk-dependent growth, survival and sensitivity towards metformin in breast cancer bone metastasis.
abstract: The mechanisms underlying reprogramming of growth factor signaling and metabolic pathways during bone metastasis of breast cancer are not clear. The Runt-related transcription factor (Runx2) regulates cell signaling during mammary epithelial morphogenesis and promotes invasion; therefore, we investigated its role in cell growth and metabolic signaling in bone-seeking breast cancer cells. We performed systemic inoculation of control or Runx2 knockdown invasive MDA-MB-231 cells in NOD/SCID mice, and compared parental and bone-derived variants for phenotypic and molecular alterations. The Runx2 knockdown showed early (0-2 weeks) inhibition of metastatic spread but late (4-6 weeks) outgrowth, suggesting Runx2-dependent bi-phasic response and reprogramming of metastatic cells. The late-stage tumor outgrowth of bone-derived Runx2 knockdown cells was associated with increased insulin-like growth factor- 1Rβ (IGF-1Rβ) levels. Interestingly, glucose uptake and glycolysis were reduced in the bone-derived Runx2 knockdown cells that could be further reduced by extracellular-regulated protein kinase (Erk1/2) inhibition. Furthermore, the Runx2 knockdown cells displayed activation of AMP-activated protein kinase (AMPKα), the sensor of cellular metabolism. Importantly, the Runx2 knockdown in bone-derived cells resulted in increased sensitivity to both Erk1/2 inhibition and AMPKα activation by PD184161 and metformin, respectively, despite increased IGF-1Rβ and AMPKα levels. Our results reveal that Runx2 promotes metastatic spread of mammary tumor cells. The growth of late-stage tumor cells can be targeted by Runx2 knockdown in combination with Mek-Erk1/2 inhibition and metformin treatment.
authors.affiliation: Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tandon
authors.affiliation: Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Othman
authors.affiliation: Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pratap
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D000814:Aniline Compounds / Q000008:administration & dosage; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D050659:Core Binding Factor Alpha 1 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008687:Metformin / Q000008:administration & dosage; D051379:Mice; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C488185:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide; D000814:Aniline Compounds; D001549:Benzamides; D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human; D008687:Metformin; D017526:Receptor, IGF Type 1; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human