title: Down regulation of circadian clock gene Period 2 accelerates breast cancer growth by altering its daily growth rhythm.
abstract: Purpose Per2, a core circadian clock gene, has tumor suppressor properties and is mutated or down regulated in human breast cancers. We have manipulated the expression of this gene in vitro and in vivo to more fully understand how the Per2 clock gene product affects cancer growth. Methods We used siRNA and shRNA to down regulate Per2 expression in vitro and in vivo and measured cancer cell proliferation, tumor growth rate and several molecular pathways relevant to cancer growth and their circadian organizations. All statistical tests were two-sided. Results Down regulation of functional Per2 gene expression increases Cyclin D and Cyclin E levels and doubles in vitro breast cancer cell proliferation (P < 0.05). Down regulation of Per2 also accelerates in vivo tumor growth and doubles the daily amplitude of the tumor growth rhythm (P < 0.05). Conclusions The clock gene Per2 exerts its tumor suppressor function in a circadian time dependent manner. Therefore, Per2 and perhaps other clock genes represent a new class of potential therapeutic targets whose manipulation will modulate cancer growth and cancer cell proliferation.
authors.affiliation: Medical Chronobiology Laboratory, WJB Dorn VA Medical Center, 6439 Garners Ferry Road, Columbia, SC 29209, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yang
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Wood
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Oh
authors.forename: Jovelyn
authors.initials: J
authors.lastname: Du-Quiton
authors.forename: Christine M
authors.initials: CM
authors.lastname: Ansell
authors.forename: William J M
authors.initials: WJ
authors.lastname: Hrushesky
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002940:Circadian Rhythm / Q000235:genetics*; D056741:Cyclin D; D019927:Cyclin E / Q000096:biosynthesis; D016213:Cyclins / Q000096:biosynthesis; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D056950:Period Circadian Proteins; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors