Registered report: the androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man.

Denise Chronscinski,Joelle Lomax,Elizabeth Iorns,Srujana Cherukeri,Fraser Tan,Nicole Perfito

doi:10.7717/peerj.1231

Abstract

The Prostate Cancer Foundation-Movember Foundation Reproducibility Initiative (PCFMFRI) seeks to address growing concerns about reproducibility in scientific research by conducting replications of recent papers in the field of prostate cancer. This Registered Report describes the proposed replication plan of key experiments from “The Androgen Receptor Induces a Distinct Transcriptional Program in Castration-Resistant Prostate Cancer in Man” by Sharma and colleagues (2013), published in Cancer Cell in 2013. Of thousands of targets for the androgen receptor (AR), the authors elucidated a subset of 16 core genes that were consistently downregulated with castration and re-emerged with castration resistance. These 16 AR binding sites were distinct from those observed in cells in culture. The authors suggested that cellular context can have dramatic effects on downstream transcriptional regulation of AR binding sites. The present study will attempt to replicate Fig. 7C by comparing gene expression of the 16 core genes identified by Sharma and colleagues in xenograft tumor tissue compared to androgen treated LNCaP cells in vitro. The Prostate Cancer Foundation-Movember Foundation Reproducibility Initiative is a collaboration between the Prostate Cancer Foundation, the Movember Initiative, and Science Exchange, and the results of the replications will be published by PeerJ.

Highlights

In tissues where it is expressed, the ligand-activated androgen receptor (AR) binds to DNA response elements and directs expression of cell- and tissue- specific genes (Kang, Janne & Palvimo, 2004; Wang, Carroll & Brown, 2005)
Prostate cancer (PC) cells depend on steroid hormones and AR to mediate oncogenic growth (Wang et al, 2009), and one of the key treatments for prostate cancer following surgery and radiation therapy is androgen deprivation therapy (ADT)
The disease often returns despite ADT; it is termed castration-resistant prostate cancer (CRPC), an aggressive and fatal form of prostate cancer

Summary

INTRODUCTION

In tissues where it is expressed, the ligand-activated androgen receptor (AR) binds to DNA response elements and directs expression of cell- and tissue- specific genes (Kang, Janne & Palvimo, 2004; Wang, Carroll & Brown, 2005). Functional outcomes of these alterations include increased AR mRNA and protein in CRPC cells (Yuan et al, 2014), the ability for other hormones to bind AR (Taplin et al, 1999), generation of ligand independent constitutively active AR variants (Ware et al, 2014; Ferraldeschi et al, 2015), and increased sensitivity of AR by posttranslational modifications (Guo et al, 2006) In their 2013 Cancer Cell paper, Sharma and colleagues (2013) used chromatin immunoprecipitation sequencing (ChIP-seq) to identify genome-wide binding targets of AR in prostate tissue from patients with CRPC, ADT-responsive PC, or untreated PC, compared with benign prostate hyperplasia. An antibody targeting TM4SF1 reduced human prostate cancer cells in matrigel implants in vivo (Lin et al, 2014)

MATERIALS & METHODS

Findings

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