Role of KCNMA1 in Breast Cancer 英文参考文献.docVIP

RoleofKCNMA1inBreastCancer MartinOeggerli1*,YueminTian2,ChristianRuiz1,BarbaraWijker1,GuidoSauter3,EllenObermann1, UweGu¨th4,IntiZlobec5,MatthiasSausbier6,KarlKunzelmann2,LukasBubendorf1 1Institute of Pathology, University of Basel, Basel, Switzerland, 2Institute of Physiology, University of Regensburg, Regensburg, Germany, 3Institute of Pathology, UniversityMedicalCenterHamburg-Eppendorf,Hamburg,Germany,4DepartmentofGynecologyandObstetrics,UniversityHospitalBasel,Basel,Switzerland,5Institute ofPathology,UniversityofBern,Bern,Switzerland,6InstituteofPharmacy,UniversityofTu¨bingen,Tu¨bingen,Germany Abstract KCNMA1encodesthea-subunitofthelargeconductance,voltageandCa2+-activated(BK)potassiumchannelandhasbeen reported as a target gene of genomic amplification at 10q22 in prostate cancer. To investigate the prevalence of the amplification in other human cancers, the copy number of KCNMA1 was analyzed by fluorescence-in-situ-hybridization (FISH) in 2,445 tumors across 118 different tumor types. Amplification of KCNMA1 was restricted to a small but distinct fractionofbreast,ovarianandendometrialcancerwiththehighestprevalenceininvasiveductalbreastcancersandserous carcinoma of ovary and endometrium (3–7%). We performed an extensive analysis on breast cancer tissue microarrays (TMA)of1,200tumorslinkedtoprognosis.KCNMA1amplificationwassignificantlyassociatedwithhightumorstage,high grade, high tumor cell proliferation, and poor prognosis. Immunofluorescence revealed moderate or strong KCNMA1 proteinexpressionin8outof9humanbreastcancersandinthebreastcancercelllineMFM223.KCNMA1-functioninbreast cancercelllineswasconfirmedbywhole-cellpatchclamprecordingsandproliferationassays,usingsiRNA-knockdown,BK channel activators such as 17?-estradiol and the BK-channel blocker paxilline. Our findings revealed that enhanced expressionofKCNMA1correlateswithandcontributestohighproliferationrateandmalignancyofbreastcancer. Citation:OeggerliM,TianY,RuizC,WijkerB,SauterG,etal.(2012)RoleofKCNMA1