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

Abstract

Chromatin coregulators are important players in tumorigenesis and cancer progression. ANCCA is an AAA+ ATPase-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 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 breast cancer cells and that it controls 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 therapeutic target for triple-negative cancers.