ATAD2 overexpression links to enrichment of B-MYB-translational signatures and development of aggressive endometrial carcinoma.

Camilla Krakstad,Anne M Øyan,Jone Trovik,Karl-Henning Kalland,Henrica M Werner,Helga B Salvesen,Hong-Wu Chen,Anna Berg,Ingunn Stefansson,Kanthida Kusonmano,Mari K Halle,Maria B Ræder,Ingvild L Tangen,Erling A Hoivik,June X Zou

doi:10.18632/oncotarget.4955

Camilla Krakstad, Anne M Øyan + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.4955

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Abstract

We have explored the potential for clinical implementation of ATAD2 as a biomarker for aggressive endometrial cancer by investigating to what extent immunohistochemical (IHC) staining for ATAD2 is feasible, reflects clinical phenotype and molecular subgroups of endometrial carcinomas. Increased expression of the ATAD2 gene has been implicated in cancer development and progression in a number of tissues, but few studies have investigated ATAD2 expression using IHC. Here we show that high ATAD2 protein expression is significantly associated with established clinical-pathological variables for aggressive endometrial cancer, also in the subset of estrogen receptor α (ERα) positive tumors. Protein and mRNA expression of ATAD2 were highly correlated (P < 0.001), suggesting that IHC staining may represent a more clinically applicable measure of ATAD2 level in routinely collected formalin fixed paraffin embedded specimens. Gene expression alterations in samples with high ATAD2 expression revealed upregulation of several cancer-related genes (B-MYB, CDCs, E2Fs) and gene sets that previously have been linked to aggressive disease and potential for new targeting therapies. Our results support that IHC staining for ATAD2 may be a clinically applicable biomarker reflecting clinical phenotype and targetable alterations in endometrial carcinomas to be further explored in controlled clinical trials.

Highlights

One of today’s most important clinical challenges is to develop clinically applicable and robust biomarkers to predict prognosis and to select patients for customized systemic treatments more likely to be beneficiary [1, 2].Endometrial cancer is one of the most common female cancers in industrialized countries, with rising incidencerate
High ATAD2 expression has been linked to aggressive disease in breast cancer and endometrial cancer but little is known regarding the variation in ATAD2 mRNA expression related to different stages of disease development for endometrial cancer
We investigated the mRNA levels of ATAD2 in a unique collection of fresh tissue from 18 precursor cancer lesions, 141 primary endometrial cancer lesions of the endometrioid subtype and 34 of non-endometrioid subtypes, as well as 42 metastatic lesions (Figure 1)

Summary

Introduction

One of today’s most important clinical challenges is to develop clinically applicable and robust biomarkers to predict prognosis and to select patients for customized systemic treatments more likely to be beneficiary [1, 2].Endometrial cancer is one of the most common female cancers in industrialized countries, with rising incidencerate. More robust biomarkers that independently can predict prognosis in order to improve treatment of endometrial cancer need to be developed [3]. The gene ATAD2 (ATPase family, AAA domain containing 2; listed as ANCCA, pro2000) is predominantly expressed in male germ cells, but becomes overexpressed in several cancer forms. It was initially identified as a target gene of the proto-oncogene AIB1 and as a transcriptional coactivator of ERα in breast cancer cells [4]. Its elevated transcripts were early included in a number of prognostic cancer-gene signatures that are linked to cancer development and progression such as increased risks of distant metastasis in breast cancer [9, 10] and disease recurrence in endometrial cancer [11]

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