title: The Distinct Gene Regulatory Network of Myoglobin in Prostate and Breast Cancer.
abstract: Myoglobin (MB) is not only strongly expressed in myocytes, but also at much lower levels in different cancer entities. 40% of breast tumors are MB-positive, with the globin being co-expressed with markers of tumor hypoxia in a proportion of cases. In breast cancer, MB expression is associated with a positive hormone receptor status and patient prognosis. In prostate cancer, another hormone-dependent cancer type, 53% of tumors were recently shown to express MB. Especially in more aggressive prostate cancer specimen MB expression also correlates with increased patient survival rates. Both findings might be due to tumor-suppressing properties of MB in cancer cells. In contrast to muscle, MB transcription in breast and prostate cancer mainly depends on a novel, alternative promoter site. We show here that its associated transcripts can be upregulated by hypoxia and downregulated by estrogens and androgens in MCF7 breast and LNCaP prostate cancer cells, respectively. Bioinformatic data mining of epigenetic histone marks and experimental verification reveal a hitherto uncharacterized transcriptional network that drives the regulation of the MB gene in cancer cells. We identified candidate hormone-receptor binding elements that may interact with the cancer-associated MB promoter to decrease its activity in breast and prostate cancer cells. Additionally, a regulatory element, 250 kb downstream of the promoter, acts as a hypoxia-inducible site within the transcriptional machinery. Understanding the distinct regulation of MB in tumors will improve unraveling the respiratory protein's function in the cancer context and may provide new starting points for developing therapeutic strategies.
authors.affiliation: Institute of Molecular Genetics, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Bicker
authors.affiliation: Institute of Molecular Genetics, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Brahmer
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Meller
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.affiliation: Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.|Regenerative Medicine Program, University and University Hospital Zurich, Zurich, Switzerland.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gorr
authors.affiliation: Institute of Molecular Genetics, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hankeln
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D019295:Computational Biology; D057225:Data Mining; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005809:Genes, Regulator; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D009211:Myoglobin / Q000235:genetics* / Q000378:metabolism*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002843:Chromatin; D009211:Myoglobin