ANCCA/ATAD2 overexpression identifies breast cancer patients with poor prognosis, acting to drive proliferation and survival of triple-negative cells through control of B-Myb and EZH2.
Chromatin coregulators are important factors in tumorigenesis and cancer progression. ANCCA is an AAA+ ATPase and a bromodomain-containing nuclear coactivator for the estrogen and androgen receptors that is crucial for assembly of chromatin-modifying complexes and proliferation of hormone-responsive cancer cells. In this study, we show that ANCCA is overexpressed in >70% of breast tumors and that its high protein level correlates well with tumor histologic grades (P<0.0001), highlighting ANCCA as a prognostic factor for poor overall survival and disease recurrence. Strikingly, high-level ANCCA correlated with triple-negative tumors that represent highly aggressive disease. Analysis of ANCCA transcript levels in multiple expression profiles of breast cancer identified ANCCA as a common signature gene, indicating that elevated transcripts also strongly correlate with tumor metastasis and poor survival. Biological and mechanistic investigations revealed that ANCCA is crucial for proliferation and survival of triple-negative/basal-like cancer cells and that it controls the expression of B-Myb, histone methyltransferase EZH2, and an Rb-E2F core program for proliferation, along with a subset of key mitotic kinesins and cell survival genes (IRS2, VEGF, and Akt1). In particular, ANCCA overexpression correlated strongly with EZH2 in tumors. Our results suggest that ANCCA may integrate multiple oncogenic programs in breast cancer, serving in particular as a prognostic marker and a therapeutic target for triple-negative cancers.
Kalashnikova
Ekaterina V
EV
Department of Biochemistry and Molecular Medicine, School of Medicine, and UC Davis Cancer Center/Basic Sciences, University of California at Davis, Sacramento, California 95817, USA.
Revenko
Alexey S
AS
Gemo
Abigael T
AT
Andrews
Nicolas P
NP
Tepper
Clifford G
CG
Zou
June X
JX
Cardiff
Robert D
RD
Borowsky
Alexander D
AD
Chen
Hong-Wu
HW
D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D020411:Oligonucleotide Array Sequence Analysis; D063151:Polycomb Repressive Complex 2; D011379:Prognosis; D034622:RNA Interference; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C064352:MYBL2 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D000251:Adenosine Triphosphatases; C544857:ATAD2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities