[en] Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERRalpha) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRalpha expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-function/loss-of-function CRPC models in vivo and in vitro. Increased levels of ERRalpha in tumor cells led to rapid tumor progression, with both bone destruction and formation, and direct impacts on osteoclasts and osteoblasts. VEGF-A, WNT5A and TGFbeta1 were upregulated by ERRalpha in tumor cells and all of these factors also significantly and positively correlated withERRalpha expression in CRPC patient specimens. Finally, high levels of ERRalpha in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERRalpha regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERRalpha is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERRalpha may constitute a new therapeutic strategy for prostate cancer skeletal-related events.
Tang YS and Allistona, T. Regulation of postnatal bone homeostasis by TGFβ. Bonekey Rep. 2013; 2(255).
Hall CL, Bafico A, Dai J, Aaronson SA, Keller ET. Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res. 2005; 65:7554-60.
Malanchi I, Santamaria-Martínez A, Susanto E, Peng H, Lehr H, Delaloye J, Huelsken J. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature. 2011; 481:85-9.
Liu AY, Zheng H, Ouyang G. Periostin, a multifunctional matricellular protein in inflammatory and tumor microenvironments. Matrix Biol. 2014; 37:150-6.
özdemir B, Hensel J, Secondini C, Wetterwald A, Schwaninger R, Fleischmann A, Raffelsberger W, Poch O, Delorenzi M, Temanni R, Mills IG, van der Pluijm G, Thalmann GN, et al. The molecular signature of the stroma response in prostate cancer-induced osteoblastic bone metastasis highlights expansion of hematopoietic and prostate epithelial stem cell niches. PLoS One. 2014; 9.
Ghajar CM PH, Mori H, Matei IR, Evason KJ, Brazier H, Almeida D, Koller A HK, Stainier DY, Chen EI, Lyden D, Bissell MJ. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol. 2013; 15:807-17.
Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud TJ, Schwabe J, Sladek F, Tsai MJ, Laudet V. International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev. 2006; 58:798-836.
Giguere V, Yang N, Segui P, Evans RM. Identification of a new class of steroid hormone receptors. Nature. 1988; 331:91-4.
Kallen J, Schlaeppi JM, Bitsch F, Filipuzzi I, Schilb A, Riou V, Graham A, Strauss A, Geiser M, Fournier B. Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor alpha (ERRalpha): crystal structure of ERRalpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1alpha. J Biol Chem. 2004; 279:49330-7.
Wei W, Schwaid A, Wang X, Wang X, Chen S, Chu Q, Saghatelian A, Wan Y. Ligand Activation of ERRa by Cholesterol Mediates Statin and Bisphosphonate Effects. Cell Metab. 2016; 23:479-91.
Busch BB, Stevens WC Jr, Martin R, Ordentlich P, Zhou S, Sapp DW, Horlick RA, Mohan R. Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha. J Med Chem. 2004; 47:5593-6.
Ariazi EA, Clark GM, Mertz JE. Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human breast cancer. Cancer Res. 2002; 62:6510-8.
Fujimura T, Takahashi S, Urano T, Kumagai J, Ogushi T, Horie-Inoue K, Ouchi Y, Kitamura T, Muramatsu M, Inoue S. Increased expression of estrogen-related receptor alpha (ERRalpha) is a negative prognostic predictor in human prostate cancer. Int J Cancer. 2007; 120:2325-30.
Zou C, Yu S, Xu Z, Wu D, Ng C, Yao X, Yew DT, Vanacker JM, Chan FL. ERRa augments HIF-1 signalling by directly interacting with HIF-1a in normoxic and hypoxic prostate cancer cells. J Pathol. 2014; 233:61-73.
Teyssier C, Bianco S, Lanvin O, Vanacker JM. The orphan receptor ERRalpha interferes with steroid signaling. Nucleic Acids Res. 2008; 36:5350-61.
Bonnelye E, Aubin JE. An energetic orphan in an endocrine tissue: a revised perspective of the function of estrogen receptor-related receptor alpha in bone and cartilage. J Bone Min Res. 2013; 28:225-33.
Fradet A, Sorel H, Bouazza L, Goehrig D, Depalle B, Bellahcene A, Castronovo V, Follet H, Descotes F, Aubin JE, Clezardin P, Bonnelye E. Dual function of ERRalpha in breast cancer and bone metastasis formation: implication of VEGF and osteoprotegerin. Cancer Res. 2011; 71:5728-38.
Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, Beltran H, Abida W, Bradley RK, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161:1215-28.
Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010; 18:11-22.
Chandran U, Ma C, Dhir R, Bisceglia M, Lyons-Weiler M, Liang W, Michalopoulos G, Becich M, Monzon FA. Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process. BMC Cancer. 2007; 12:64.
Cai C, Wang H, He HH, Chen S, He L, Ma F, Mucci L, Wang Q, Fiore C, Sowalsky AG, Loda M, Liu XS, Brown M, et al. ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancer. J Clin Invest. 2013; 123:1109-23.
Akech J, Wixted JJ, Bedard K, van der Deen M, Hussain S, Guise TA, van Wijnen AJ, Stein JL, Languino LR, Altieri DC, Pratap J, Keller E, Stein GS, et al. Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene. 2010; 29:811-21.
Fradet A SH, Depalle B, Serre CM, Farlay D, Turtoi A, Bellahcene A, Follet HCV, Clézardin P, Bonnelye E. A new murine model of osteoblastic/osteolytic lesions from human androgen-resistant prostate cancer. PLoS One. 2013; 8:e75092.
LeRoy BE, Thudi NK, Nadella MV, Toribio RE, Tannehill-Gregg SH, van Bokhoven A, Davis D, Corn S, Rosol TJ. New bone formation and osteolysis by a metastatic, highly invasive canine prostate carcinoma xenograft. Prostate. 2006; 66:1213-22.
Stein RA, Gaillard S, McDonnell DP. Estrogen-related receptor alpha induces the expression of vascular endothelial growth factor in breast cancer cells. J Steroid Biochem Mol Biol. 2009; 114:106-12.
Bonnelye E, Merdad L, Kung V, Aubin JE. The orphan nuclear estrogen receptor-related receptor alpha (ERRalpha) is expressed throughout osteoblast differentiation and regulates bone formation in vitro. J Cell Biol. 2001; 153:971-84.
Zelzer E OB. Multiple roles of vascular endothelial growth factor (VEGF) in skeletal development, growth, and repair. Curr Top Dev Biol. 2005; 169-87.
Hu K, Olsen BR. Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J Clin Invest. 2016; 126:509-26.
Larson S, Zhang X, Dumpit R, Coleman I, Lakely B, Roudier M, Higano CS, True LD, Lange PH, Montgomery B, Corey E, Nelson PS, Vessella RL, et al. Characterization of osteoblastic and osteolytic proteins in prostate cancer bone metastases. Prostate. 2013; 73: 932-40.
Haider M, Zhang X, Coleman I, Ericson N, True LD, Lam HM, Brown LG, Ketchanji M, Nghiem B, Lakely B, Coleman R, Montgomery B, Lange PH1, et al. Epithelial mesenchymal-like transition occurs in a subset of cells in castration resistant prostate cancer bone metastases. Clin Exp Metastasis. 2016; 33:239-48.
Hornberg E, Ylitalo EB, Crnalic S, Antti H, Stattin P, Widmark A, Bergh A, Wikstrom P. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS One. 2011; 6:e19059.
Maeda K, Kobayashi Y, Udagawa N, Uehara S, Ishihara A, Mizoguchi T, Kikuchi Y, Takada I, Kato S, Kani S. Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med. 2012; 18:405-12.
Auld KL, Berasi SP, Liu Y, Cain M, Zhang Y, Huard C, Fukayama S, Zhang J, Choe S, Zhong W, Bhat B.M, Bhat RA, Brown EL, et al. Estrogen-related receptor alpha regulates osteoblast differentiation via Wnt/beta-catenin signaling. J Mol Endocrinol. 2012; 48:177-91.
Kusumbe AP, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. 2014; 507:323-8.
Bellon M, Ko N, Lee M, Yao Y, Waldmann T, Trepel J, Nicot C. Adult T-cell leukemia cells overexpress Wnt5a and promote osteoclast differentiation. Blood. 2013; 121:5045-54.
Kobayashi Y, Uehara S, Udagawa N, Takahashi N. Regulation of bone metabolism by Wnt signals. J Biochem. 2016; 159:387-92.
Fournier PGJ, Juárez P, Jiang G, Clines GA, Niewolna M, Kim HS, Walton HW, Peng XH, Liu Y, Mohammad KS, Wells CD, Chirgwin JM, Guise TA. The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone. Cancer Cell. 2015; 27:809-21.
Dwyer MA, Joseph JD, Wade HE, Eaton ML, Kunder RS, Kazmin D, Chang CY, McDonnel DP. WNT11 expression is induced by estrogen-related receptor alpha and beta-catenin and acts in an autocrine manner to increase cancer cell migration. Cancer Res. 2010; 70:9298-308.
Kikuchi A, Yamamoto H, Sato A, Matsumoto S. Wnt5a: its signalling, functions and implication in diseases. 2012; Acta Physiol(204):1.
Weeraratna A, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, Trent JM. Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell. 2002; 1:279-88.
Miyamoto D, Zheng Y, Wittner BS, Lee RJ, Zhu H, Broderick KT, Desai R, Fox DB, Brannigan BW, Trautwein J, Arora KS, Desai N, Dahl DM, et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. 2015; 349:1351-6.
Lee G, Kang DI, Ha YS, Jung YS, Chung J, Min K, Kim TH, Moon KH, Chung JM, Lee DH, Kim WJ, Kim IY. Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP-6 induction. Br J Cancer. 2014 18; 110:1634-44.
Thiele S, Göbel A, Rachner TD, Fuessel S, Froehner M, Muders MH, Baretton GB, Bernhardt R, Jakob F, Glüer CC, Bornhäuser M, Rauner M, Hofbauer LC. WNT5A has anti-prostate cancer effects in vitro and reduces tumor growth in the skeleton in vivo. J Bone Min Res. 2015; 30:471-80.
Nuzzo PV, Buzzatti G, Ricci F, Rubagotti A, Argellati F, Zinoli L, Boccardo F. Periostin: a novel prognostic and therapeutic target for genitourinary cancer? Clin Genitourin Cancer. 2014; 12:301-11.
Torrano V, Valcarcel-Jimenez L, Cortazar AR, Liu X, Urosevic J, Castillo-Martin M, Fernández-Ruiz S, Morciano G, Caro-Maldonado t A, Pandya P, LA, Guiu M, Zúñiga-García P, et al. The metabolic co-regulator PGC1a suppresses prostate cancer metastasis. Nat Cell Biol. 2016; 18:645-56.
Waltregny D BA, de Leval X, Florkin B, Weidle U, Castronovo V. Increased expression of bone sialoprotein in bone metastases compared with visceral metastases in human breast and prostate cancers. J Bone Min Res. 2000; 15:834-43.