title: Endogenous myoglobin in breast cancer is hypoxia-inducible by alternative transcription and functions to impair mitochondrial activity: a role in tumor suppression?
abstract: Recently, immunohistochemical analysis of myoglobin (MB) in human breast cancer specimens has revealed a surprisingly widespread expression of MB in this nonmuscle context. The positive correlation with hypoxia-inducible factor 2α (HIF-2α) and carbonic anhydrase IX suggested that oxygen regulates myoglobin expression in breast carcinomas. Here, we report that MB mRNA and protein levels are robustly induced by prolonged hypoxia in breast cancer cell lines, in part via HIF-1/2-dependent transactivation. The hypoxia-induced MB mRNA originated from a novel alternative transcription start site 6 kb upstream of the ATG codon. MB regulation in normal and tumor tissue may thus be fundamentally different. Functionally, the knockdown of MB in MDA-MB468 breast cancer cells resulted in an unexpected increase of O(2) uptake and elevated activities of mitochondrial enzymes during hypoxia. Silencing of MB transcription attenuated proliferation rates and motility capacities of hypoxic cancer cells and, surprisingly, also fully oxygenated breast cancer cells. Endogenous MB in cancer cells is apparently involved in controlling oxidative cell energy metabolism, contrary to earlier findings on mouse heart, where the targeted disruption of the Mb gene did not effect myocardial energetics and O(2) consumption. This control function of MB seemingly impacts mitochondria and influences cell proliferation and motility, but it does so in ways not directly related to the facilitated diffusion or storage of O(2). Hypothetically, the mitochondrion-impairing role of MB in hypoxic cancer cells is part of a novel tumor-suppressive function.
authors.affiliation: Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany. glen.kristiansen@ukb.uni-bonn.de
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.forename: Junmin
authors.initials: J
authors.lastname: Hu
authors.forename: Daniela
authors.initials: D
authors.lastname: Wichmann
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Stiehl
authors.forename: Michael
authors.initials: M
authors.lastname: Rose
authors.forename: Josefine
authors.initials: J
authors.lastname: Gerhardt
authors.forename: Annette
authors.initials: A
authors.lastname: Bohnert
authors.forename: Anette
authors.initials: A
authors.lastname: ten Haaf
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: James
authors.initials: J
authors.lastname: Raleigh
authors.forename: Mahesh A
authors.initials: MA
authors.lastname: Varia
authors.forename: Patrick
authors.initials: P
authors.lastname: Subarsky
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Scandurra
authors.forename: Erich
authors.initials: E
authors.lastname: Gnaiger
authors.forename: Eva
authors.initials: E
authors.lastname: Gleixner
authors.forename: Anne
authors.initials: A
authors.lastname: Bicker
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Hankeln
authors.forename: Edgar
authors.initials: E
authors.lastname: Dahl
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gorr
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009211:Myoglobin / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D009211:Myoglobin