title: Topoisomerase 2 Alpha Cooperates with Androgen Receptor to Contribute to Prostate Cancer Progression.
abstract: Overexpression of TOP2A is associated with risk of systemic progression in prostate cancer patients, and higher levels of TOP2A were found in hormone-resistant cases. To elucidate the mechanism by which high levels of TOP2A contribute to tumor progression we generated TOP2A overexpressing prostate cancer cell lines. We show that TOP2A promotes tumor aggressiveness by inducing chromosomal rearrangements of genes that contribute to a more invasive phenotype. Anti-androgen treatment alone was ineffective in killing TOP2A overexpressing cells due to activation of an androgen receptor network. TOP2A poisons killed tumor cells more efficiently early in the progression course, while at later stages they provided greater benefit when combined with anti-androgen therapy. Mechanistically, we find that TOP2A enhances androgen signaling by facilitating transcription of androgen responsive genes, thereby promoting tumor cell growth. These studies revealed a relationship between TOP2A and androgen receptor signaling pathway that contributes to prostate cancer progression and confers sensitivity to treatments.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.|Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: J L
authors.initials: JL
authors.lastname: Schaefer-Klein
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.|Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Murphy
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Johnson
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.|Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Vasmatzis
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America.|Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Kovtun
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000951:Antigens, Neoplasm / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness / Q000473:pathology*; D000075223:Poly-ADP-Ribose Binding Proteins; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D011944:Receptors, Androgen; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human