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FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy

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FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy Published OnlineFirst January 26, 2010; DOI: 10.1158/0008-5472.CAN-09-2515 Published Online First on January 26, 2010 as 10.1158/0008-5472.CAN-09-2515 Therapeutics, Targets, and Chemical Biology Cancer Research FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy Hayley D. McKeen1, Christopher Byrne1, Puthen V. Jithesh2, Christopher Donley1, Andrea Valentine1, Anita Yakkundi1, Martin O'Rourke1, Charles Swanton3,4, Helen O. McCarthy1, David G. Hirst1, and Tracy Robson1 Abstract The HSP90 chaperone and immunophilin FKBPL is an estrogen-responsive gene that interacts with estogen receptor α (ERα) and regulates its levels. In this study, we explored the effects of FKBPL on breast cancer proliferation. Breast cancer cells stably overexpressing FKBPL became dependent on estrogen for their growth and were dramatically more sensitive to the antiestrogens tamoxifen and fulvestrant, whereas FKBPL knock- down reverses this phenotype. FKBPL knockdown also decreased the levels of the cell cycle inhibitor p21WAF1 and increased ERα phosphorylation on Ser118 in response to 17β-estradiol and tamoxifen. In support of the likelihood that these effects explained FKBPL-mediated cell growth inhibition and sensitivity to endocrine therapies, FKBPL expression was correlated with increased overall survival and distant metastasis-free survival in breast cancer patients. Our findings suggest that FKBPL may have prognostic value based on its impact on tumor proliferative capacity and sensitivity to endocrine therapies, which improve outcome. Cancer Res; 70(3); 1090–100. ©2010 AACR. Introduction ER-positive tumors do not respond to hormone therapy and 30% to 40% of patients who initially respond positively re- The steroid hormone estrogen has a pivotal role in tumor lapse within 5 years. Therefore, other proteins involved in development (1), with increased levels of circulating estrogen ER signaling need to be assessed as potential targets for ther- being linked with initiation and progression of breast cancer apeutic intervention. (2–4). Estrogen receptors (ER) are members of the nuclear We have previously isolated, and partially characterized, receptor superfamily of ligand-activated transcription factors FKBPL (DIR1/Wisp39). We showed that it belongs to the im- that mediate the biological effects of estrogen (5). Ligand munophilin/FKBP protein family as a consequence of the binding causes the receptor to dimerize and activate or re- presence of COOH-terminal tetratricopeptide repeat do- press transcription of ER target genes through recruitment of mains (TPR) and a partial peptidyl-prolyl cis-trans isomerase coregulators (6). Around two thirds of breast tumors express (PPIase) domain (10, 11). The TPR domains of immunophilin ERα and are therefore dependent on estrogen for their proteins are particularly important for binding to the molec- growth. Anticancer drugs such as tamoxifen exert their anti- ular chaperone Hsp90 (12). In support of this association, tumor activity through binding ERα, blocking the interaction FKBPL has been implicated in Hsp90-dependent stabilization between estrogen and its receptor (7), and altering its confor- of newly synthesized p21 by preventing its proteosomal deg- mation, leading to corepressor recruitment to the complex radation (13); also, overexpression of FKBPL inhibits cell cy- (8, 9). This results in inhibition of ERα-regulated genes that cle progression at the G0-G1 phase in leukemic cells (14). promote tumor growth. However, despite the success of this More recently, a role for FKBPL in Hsp90-associated steroid group of agents in the clinic, almost half of the patients with hormone receptor complexes was identified in which FKBPL regulated glucocorticoid receptor (GR) protein levels, tran- scriptional activation, and cellular localization in prostate Authors' Affiliations: 1School of Pharmacy, McClay Research Centre and 2Centre for Cancer Research and Cell Biology, Queen's University, cancer cells (15). Belfast, Northern Ireland, United Kingdom; 3Cancer Research UK London In breast cancer, immunophilins and other cochaperones Research Institute, London, United Kingdom; and 4Breast Unit, have been shown to influence ER signaling. To maintain re- Department of Medicine, Royal Marsden Hospital, Sutton, United α Kingdom ceptor stability in the absence of ligand, ER exists in a mo- lecular complex with Hsp90, p23, and the immunophilins Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). FKBP52 or Cyp40 (16). The immunophilins competitively H.D. McKeen and C. Byrne contributed equally to this work. bind Hsp90 through TPR domains (12), and cochaperone re- cruitment is a dynamic process that controls steroid receptor Corresponding Author: Tracy Robson, School of Pharmacy, McClay Research Centre, Queen's University, 97 Lisburn Road, Belfast, Northern activity in a tissue-specific manner. Cyp40 and FKBP52 are Ireland BT9 7BL, United Kingdom. Phone: 44-028-90972360; Fax: 44- overexpressed in breast tumors (17) and are upregulated 028-90247794; E-mail: [email protected]. transcriptionally and posttranscriptionally by estrogen, doi: 10.1158/0008-5472.CAN-09-2515 whereas exposure to the pure estrogen antagonist ICI ©2010 American Association for Cancer Research. 182,780 (fulvestrant) prevents this estrogen-mediated 1090 Cancer Res; 70(3) February 1, 2010 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst January 26, 2010; DOI: 10.1158/0008-5472.CAN-09-2515 FKBPL Modulates the Estrogen Receptor Signaling Pathway increase (18). A recent study has found that the FKBP52 gene Mammalian two-hybrid assay. The CheckMate Mamma- is methylated in ER-negative MDA-MB-231 but not in ER- lian Two-Hybrid System (Promega) was used to assess pro- positive MCF7 cells, suggesting that repression of FKBP52 tein interactions. In-frame cloning of full-length FKBPL into may itself affect ER expression (19). Furthermore, Hsp90 the pBIND-GAL4 binding domain plasmid and Hsp90 into and immunophilin ligands have been shown to target ER the herpes simplex viral protein 16 (pACT-VP16) activation for proteosomal degradation (20). The Hsp90 cochaperone domain plasmid were carried out according to the manu- p23 also plays an important role in ER signal transduction facturer's instructions. MCF-7 cells at 60% to 80% con- (21) and regulates the ER target genes pS2 and cathepsin fluency were transfected with either of these plasmids or D, promoting tumor cell adhesion and invasion (22). the pACT-MyoD and pBIND-Id positive control plasmids Hsp90 and its cochaperones clearly play a role in ER sig- along with the firefly luciferase pG5luc plasmid using naling; however, a role for FKBPL in these ER-associated Lipofectamine Plus according to the manufacturer's instruc- complexes has not yet been described. Understanding the tions. After 24 h, cells were analyzed using the Dual-Glo Lu- possible role of this immunophilin in the ERα-Hsp90 com- ciferase Assay System (Promega). Firefly luciferase activity plex might shed further light on ER signaling. This is espe- was normalized to Renilla luciferase activity and presented cially important because the biological mechanisms as relative light units. Three independent experiments were underlying de novo and acquired tamoxifen resistance have performed with triplicates for each experiment. not been fully elucidated. Previous studies have linked endo- Coimmunoprecipitations. MCF7 or 3.1D2 cells were crine therapy resistance with increased activity of epidermal grown to 90% confluency, washed twice with ice-cold PBS, growth factor receptor (EGFR), human epidermal growth fac- and lysed in buffer [20 mmol/L Tris-HCl (pH 7.4), 1% Igepal, tor receptor 2, and phosphatidylinositol 3-kinase pathways; 12 mmol/L sodium deoxycholate, 0.1% SDS, 10 mmol/L sodi- modification of ER phosphorylation status; deregulation of um molybdate, 1 protease inhibitor tablet] for 30 min on ice, cell cycle proteins (23); and inhibition of CDK10 (24) and then pelleted by centrifugation at 13,000 rpm for 5 min at 4° BRCA1 (25). Here, we show that FKBPL is an estrogen-induc- C. One fifth of the lysate was removed to a fresh tube for use ible gene that acts as a cochaperone in ERα/Hsp90 molecular as whole cell lysate positive control for the Western blots. complexes; furthermore, FKBPL levels may be both a prog- The remaining lysates were precleared by incubating with nostic indicator and determinant of response to endocrine prewashed agarose G beads for 1 h at 4°C with rotation therapy. and then lysates were incubated with Hsp90, FKBPL, ERα, or IgG (negative control) antibody–bound Protein G-Sephar- Materials and Methods ose beads (Cancer Research UK) at 4°C overnight. The beads were washed three times in ice-cold lysis buffer and twice in Cell culture and transfections. The ER-positive cell lines ice-cold PBS then resuspended in 2× Laemmli buffer. West- MCF7 and T47D were obtained from Cancer Research UK ern blot analysis was then carried out. and American Type Culture Collection, respectively, and Western blot analysis. Samples were subjected to SDS- maintained as monolayers in DMEM (Invitrogen) supple- PAGE electrophoresis using the XCell Surelock Mini-Cell Sys- mented with 10% FCS. Cell lines were authenticated by tem (Invitrogen), transferred onto nitrocellulose membranes, short tandem repeat (STR) profiling carried out by the blocked for 1 h at room temperature
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