Expression and Function of Androgen Receptor Coactivator p44/Mep50/WDR77 in Ovarian Cancer Martin Ligr 1. , Ruzeen Rohintan Patwa 1. , Garrett Daniels 1 , Lorraine Pan 1 , Xinyu Wu 1 , Yirong Li 1 , Liantian Tian 1 , Zhenxing Wang 7 , Ruliang Xu 1 , Jingjing Wu 5 , Fan Chen 1 , Jinsong Liu 6 , Jian-Jun Wei 5 *, Peng Lee 1,2,3,4 * 1 Department of Pathology, New York University School of Medicine, New York, New York, United States of America, 2 Department of Urology, New York University School of Medicine, New York, New York, United States of America, 3 NYU Cancer Institute, New York University School of Medicine, New York, New York, United States of America, 4 New York Harbor Healthcare System, New York, New York, United States of America, 5 Department of Pathology, Northwestern University School of Medicine, Chicago, Illinois, United States of America, 6 Department of Pathology, M. D. Anderson Cancer Center, Houston, Texas, United States of America, 7 Department of Cancer Biology, M. D. Anderson Cancer Center, Houston, Texas, United States of America Abstract Hormones, including estrogen and progesterone, and their receptors play an important role in the development and progression of ovarian carcinoma. Androgen, its receptor and coactivators have also been implicated in these processes. p44/Mep50/WDR77 was identified as a subunit of the methylosome complex and lately characterized as a steroid receptor coactivator that enhances androgen receptor as well as estrogen receptor-mediated transcriptional activity in a ligand- dependent manner. We previously described distinct expression and function of p44 in prostate, testis, and breast cancers. In this report, we examined the expression and function of p44 in ovarian cancer. In contrast to findings in prostate and testicular cancer and similar to breast cancer, p44 shows strong cytoplasmic localization in morphologically normal ovarian surface and fallopian tube epithelia, while nuclear p44 is observed in invasive ovarian carcinoma. We observed that p44 can serve as a coactivator of both androgen receptor (AR) and estrogen receptor (ER) in ovarian cells. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in ovarian cancer cells in the presence of estrogen or androgen. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during ovarian tumorigenesis. Citation: Ligr M, Patwa RR, Daniels G, Pan L, Wu X, et al. (2011) Expression and Function of Androgen Receptor Coactivator p44/Mep50/WDR77 in Ovarian Cancer. PLoS ONE 6(10): e26250. doi:10.1371/journal.pone.0026250 Editor: Ilya Ulasov, University of Chicago, United States of America Received March 7, 2011; Accepted September 23, 2011; Published October 13, 2011 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This work was funded by Northwestern Memorial Hospital Dixon Translational Research Fund grant to JJW. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: jianjun-wei@northwestern.edu (JJW); peng.lee@nyumc.org (PL) . These authors contributed equally to this work. Introduction Ovarian cancer is the fifth leading cause of death from cancer in women, and the second most deadly gynecologic malignancy in the United States [1]. Epithelial ovarian cancer accounts for about 3% of total cancer cases in women. National Cancer Institute estimated that in 2010, 21,880 women would be diagnosed and 13,850 women would die of cancer of the ovary [2]. Ovarian cancer is a group of heterogeneous diseases and consists of different histological types, which can be readily differentiated by histological evaluation [3]. Current clinical guidelines set forth by World Health Organization distinguish eight histological tumor subtypes: papillary serous carcinoma (PSC), endometrioid carcinoma (EMC), mucinous carcinoma (MUC), clear cell carci- noma (CCC), transitional cell carcinoma (TCC), squamous cell, mixed epithelial, and undifferentiated, with serous carcinoma displaying the most malignant phenotype [4,5]. Genome-wide global gene analysis further defines distinct expression profiles of different types of ovarian cancer [6]. Different histological types of ovarian cancer seem to be regulated by different pathogenic pathways [7]. Most EMC and PSC present moderate to high levels of ER [8,9,10] and AR expression [11,12]. Steroid hormone receptors, such as ER, progesterone receptor (PR), and AR, are involved in the development of endocrine organ cancers, including ovarian cancer [12,13,14]. Estrogens are known to be regulators of growth and differentiation in normal ovaries, as well as in the development of ovarian carcinoma, but the mechanism of this hormonal regulation remains ambiguous. Estrogen acts via two nuclear receptors, estrogen receptor alpha (ERa) and estrogen receptor beta (ERb) that bind to an estrogen response element (ERE) in the promoter region of target genes, regulating their transcrip- tional activity [15]. Similarly, AR is also a ligand-activated transcriptional factor. The binding of androgen to the AR results in nuclear localization of the hormone-receptor complex together with coactivators and basal transcriptional machinery. Once in the nucleus it then binds to an androgen response element (ARE), regulating the expression of target genes [16]. AR is a prevalent sex steroid receptor expressed in ovarian cancers. Eighty-four percent of tumors express AR, as opposed to only 74% of tumors expressing ER and 41% expressing PR [17]. There is a higher risk of ovarian cancer in post menopause, at which time androgens are the primary steroids secreted by the ovary [18]. High expression of PR is associated with good prognosis in multivariant analysis for ovarian cancer [19]. However, the results PLoS ONE | www.plosone.org 1 October 2011 | Volume 6 | Issue 10 | e26250