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Expression of estrogen receptor co-regulators NCoR and PELP1 in epithelial cells and myofibroblasts of colorectal carcinomas: cytoplasmic translocation of NCoR in epithelial cells correlates with worse prognosis

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An Erratum to this article was published on 23 December 2008

An Erratum to this article was published on 23 December 2008

Abstract

Proline-, glutamic acid-, and leukine-rich protein (PELP1) is a novel co-regulatory protein that modulates genomic and non genomic actions of estrogen receptors. Nuclear receptor co-repressor (NCoR) represses estrogen-receptor-dependent transcription. PELP1 and NCoR expression was evaluated in tissue sections from 107 formalin-fixed, paraffin-embedded colectomy specimens. Normal mucosa and adenomas were also evaluated in 77 and 29 cases, respectively. PELP1 was expressed in a dot-like pattern in the nuclei of epithelial and stromal cells. Statistical analysis revealed an increase in PELP1 expression in myofibroblasts from normal mucosa through adenomas to carcinomas. NCoR was expressed in the nuclei and the cytoplasm of epithelial cells. Nuclear expression was more common in normal mucosa, whereas cytoplasmic expression was higher in malignant epithelial cells. Additionally, NCoR was expressed in the cytoplasm of cancer-associated myofibroblasts, but was rarely noted in myofibroblasts of normal mucosa or adenomas. Cytoplasmic expression of NCoR in epithelial cells correlated with better disease-free and overall survival on univariate analysis and was an independent prognostic marker for disease-free survival on multivariate analysis. These findings suggest that deregulation of co-regulators expression in both epithelial cells and myofibroblasts may contribute to the initiation and progression of colorectal carcinoma.

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References

  1. Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002 CA. Cancer J Clin 55:74–108

    Article  Google Scholar 

  2. Kampman E, Potter JD, Slattery ML et al (1997) Hormone replacement therapy, reproductive history, and colon cancer: a multicenter, case-control study in the United States. Cancer Causes Control 8:146–158

    Article  PubMed  CAS  Google Scholar 

  3. Lechner D, Kallay E, Cross HS (2005) Phytoestrogens and colorectal cancer prevention. Vitam Horm 70:169–198

    Article  PubMed  CAS  Google Scholar 

  4. Gunter MJ, Hoover DR, Yu H et al (2008) Insulin, insulin-like growth factor-I, endogenous estradiol, and risk of colorectal cancer in postmenopausal women. Cancer Res 68:329–337

    Article  PubMed  CAS  Google Scholar 

  5. Di Domenico M, Castoria G, Bilancio A et al (1996) Estradiol activation of human colon carcinoma-derived Caco-2 cell growth. Cancer Res 56:4516–4521

    PubMed  Google Scholar 

  6. Deroo B, Korach KS (2006) Estrogen receptors and human disease. J Clin Invest 116:561–570

    Article  PubMed  CAS  Google Scholar 

  7. Lonard DM, O’Malley BW (2007) Nuclear receptor coregulators: judges, juries and executioners of cellular regulation. Mol Cell 27:691–700

    Article  PubMed  CAS  Google Scholar 

  8. McKenna NJ, O’Malley BW (2002) Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108:465–474

    Article  PubMed  CAS  Google Scholar 

  9. O’Malley BW (2006) Little molecules with big goals. Science 313:1749–1750

    Article  PubMed  CAS  Google Scholar 

  10. McKenna NJ, Lanz RB, O’Malley BW (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20:321–344

    Article  PubMed  CAS  Google Scholar 

  11. Wong C-W, McNally C, Nickbarg E et al (2002) Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src Erk phosphorylation cascade. Proc Natl Acad Sci USA 99:14783–14788

    Article  PubMed  CAS  Google Scholar 

  12. Wu RC, Qin J, Yi P et al (2004) Selective phosphorylations of the SRC-3/AIB1 coactivator integrate genomic responses to multiple cellular signalling pathways. Mol Cell 15:937–949

    Article  PubMed  CAS  Google Scholar 

  13. Greger JG, Fursov N, Cooch N (2007) Phosphorylation of MNAR promotes estrogen activation of phosphatidylinositol 3-kinase. Mol Cel Biol 27:1904–1913

    Article  CAS  Google Scholar 

  14. Smith CL, O’Malley BW (2004) Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 25:45–71

    Article  PubMed  CAS  Google Scholar 

  15. Webb P, Valentine C, Nguyen P et al (2003) ERβ binds N-CoR in the presence of estrogens via an LXXLL-like motif in the N-CoR C-terminus. Nucl Recept 1:4

    Article  PubMed  Google Scholar 

  16. Fernadez-Majada V, Pujadas J, Vilardell F et al (2007) Aberrant cytoplasmic localization of N-CoR in colorectal tumors. Cell cycle 6:1748–1752

    Google Scholar 

  17. Espinosa L, Santos S, Ingles-Esteve J et al (2002) p65-NFkappaB synergizes with Notch to activate transcription by triggering cytoplasmic translocation of the nuclear receptor corepressor N-CoR. J Cell Sci 115:1295–1303

    Article  PubMed  CAS  Google Scholar 

  18. Jonas BA, Privalsky ML (2004) SMRT and N-CoR corepressors are regulated by distinct kinase signalling pathways. J Biol Chem 279:54676–54686

    Article  PubMed  CAS  Google Scholar 

  19. Rajhans R, Vadlamudi RK (2006) Comprehensive analysis of recent biochemical and biologic findings regarding a newly discovered protein-PELP1/MNAR. Clin Exp Metastasis 23:1–7

    Article  PubMed  CAS  Google Scholar 

  20. Vadlamudi RK, Wang RA, Mazumdar A et al (2001) Molecular cloning and characterization of PELP1, a novel human coregulator of estrogen receptor α. J Biol Chem 276:38272–38279

    PubMed  CAS  Google Scholar 

  21. Witz IP (2008) Yin–yang activities and vicious cycles in the tumor microenvironment. Cancer Res 68:9–13

    Article  PubMed  CAS  Google Scholar 

  22. Chang HY, Sneddon JB, Alizadeh AA et al (2004) Gene expression signature of fibroblast serum response predicts cancer progression: similarities between tumors and wounds. PLOS Biol 2:e7

    Article  PubMed  CAS  Google Scholar 

  23. West RB, Nuyten DSA, Subramanian S et al (2005) Determination of stroma signatures in breast carcinoma. PLOS Biol 3:e187

    Article  PubMed  CAS  Google Scholar 

  24. Desmoulliere A, Guyot C, Gabbiani G (2004) The stroma reaction myofibroblast: key player in the control of tumor cell behavior. Int J Dev Biol 48:509–517

    Article  Google Scholar 

  25. Nakayama H, Enzan H, Miyazaki E et al (2000) Differential expression of CD34 in normal colorectal tissue, peritumoral inflammatory tissue, and tumor stroma. J Clin Pathol 53:626–629

    Article  PubMed  CAS  Google Scholar 

  26. Adegboyega PA, Mifflin RC, DiMari JF et al (2002) Immunohistochemical study of myofibroblasts in normal colonic mucosa, hyperplastic polyps and adenomatous colorectal polyps. Arch Pathol Lab Med 126:829–836

    PubMed  Google Scholar 

  27. Chen AL, Soman KV, Rychahou PG et al (2005) Proteomic analysis of colonic myofibroblasts and effect on colon cancer cell proliferation. Surgery 138:382–390

    Article  PubMed  Google Scholar 

  28. De Wever O, Nguyen OD, Van Hoorde L et al (2004) Tenascin C and SF/HGF produced by myofibroblasts can provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J 18:1016–1028

    PubMed  Google Scholar 

  29. Sivridis E, Giatromanolaki A, Koukourakis MI (2005) Proliferating fibroblasts at the invading tumour edge of colorectal adenocarcinomas are associated with endogenous markers of hypoxia, acidity, and oxidative stress. J Clin Pathol 58:1033–1038

    Article  PubMed  CAS  Google Scholar 

  30. Liebeau B, Heymann M-F, Henry F et al (1999) Immunomodulatory effects of tumor associated fibroblasts in colorectal tumor development. Int J Cancer 81:629–636

    Article  Google Scholar 

  31. Scoville DH, Sato T, He XC et al (2008) Current view: intestinal stem cells and signaling. Gastroenterology 134:849–864

    Article  PubMed  CAS  Google Scholar 

  32. Powell DW, Mifflin RC, Valentich JD et al (1999) Mofibroblast I. Paracrine cells important in health and disease. Am J Physiol 277(1 Pt 1):C1–C9

    PubMed  CAS  Google Scholar 

  33. Cooke PS, Buchanan DL, Young P et al (1997) Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium. Proc Natl Acad Sci USA 94:6535–6540

    Article  PubMed  CAS  Google Scholar 

  34. Cunha GR, Young P, Hom YK et al (1997) Elucidation of a role for stromal steroid hormone receptors in mammary gland growth and development using tissue recombinants. J Mammary Gland Biol Neoplasia 2:393–402

    Article  PubMed  CAS  Google Scholar 

  35. Prins GS, Birch L, Couse JF et al (2001) Estrogen imprinting of the developing prostate gland is mediated through stromal estrogen receptor alpha: studies with alphaERKO and betaERKO mice. Cancer Res 61:6089–6097

    PubMed  CAS  Google Scholar 

  36. Gupta PB, Proia D, Cingoz O et al (2007) Systemic stromal effects of estrogens promote the growth of estrogen receptor-negative tumors. Cancer Res 67:2062–2071

    Article  PubMed  CAS  Google Scholar 

  37. Schurch W, Seemayer TA, Gabbiani G (1998) The myofibroblast. Am J Surg Pathol 22:141–147

    Article  PubMed  CAS  Google Scholar 

  38. Frasor J, Danes JM, Funk CC et al (2005) Estrogen down-regulation of the corepressor N-CoR: mechanism and implications for estrogen derepression of N-CoR-regulated genes. PNAS 102:13153–13157

    Article  PubMed  CAS  Google Scholar 

  39. Dobrzycka KM, Townson SM, Jiang S et al (2003) Estrogen receptor corepressors—a role in human breast cancer. Endocr Relat Cancer 10:517–536

    Article  PubMed  CAS  Google Scholar 

  40. Park DM, Li J, Okamoto H, Akeju O et al (2007) N-CoR pathway targeting induces glioblastoma derived cancer stem cell differentiation. Cell Cycle 6:467–470

    PubMed  CAS  Google Scholar 

  41. Lee M-O, Kang H-J (2002) Role of coactivators and corepressors in the induction of the RARβ gene in human colon cancer cells. Biol Pharm Bull 25:1298–1302

    Article  PubMed  CAS  Google Scholar 

  42. Hornberg JJ, Bruggeman FJ, Westerhoff HV et al (2006) Cancer: a system biology disease. Biosystems 83:81–90

    Article  PubMed  CAS  Google Scholar 

  43. Jepsen K, Hermanson OM, Onami TM et al (2000) Combinatorial roles of the nuclear receptor corepressor in transcription and development. Cell 102:753–763

    Article  PubMed  CAS  Google Scholar 

  44. Hermanson O, Jepsen K, Rosenfeld MG (2002) N-CoR controls differentiation of neural stem cells into astrocytes. Nature 419:934–939

    Article  PubMed  CAS  Google Scholar 

  45. Grignani F, De Matteis S, Nervi C et al (1998) Fusion proteins of the retinoic acid receptor-a recruit histone deacetylase in promyelocytic leukaemia. Nature 391:815–818

    Article  PubMed  CAS  Google Scholar 

  46. Fortunel NO, Otu HH, Ng HH et al (2000) Comment on “‘stemness’: transcriptional profiling of embryonic and adult stem cells” and “a stem cell molecular signature”. Science 302:393

    Article  Google Scholar 

  47. Spirakov M, Fisher AG (2007) Epigenetic signatures of stem-cell identity. Nat Rev Genet 8:263–271

    Article  CAS  Google Scholar 

  48. Vadlamudi RK, Kumar R (2007) Functional and biological properties of the nuclear receptor coregulator PELP1/MNAR. Nuclear Receptor Signaling 5:e004

    PubMed  Google Scholar 

  49. Barleta F, Wong C-W, McNally C et al (2004) Characterization of the interactions of estrogen receptor and MNAR in the activation of cSrc. Mol Endocrinol 18:1096–1108

    Article  CAS  Google Scholar 

  50. Vadlamudi RK, Manavathi B, Balasenthil S et al (2005) Functional implications of altered subcellular localization of PELP1 in breast cancer cells. Cancer Res 65:7724–7732

    PubMed  CAS  Google Scholar 

  51. Nair SS, Mishra SK, Yang Z et al (2004) Potential role of a novel transcriptional coactivators PELP1 in histone H1 displacement in cancer cells. Cancer Res 64:6416–6423

    Article  PubMed  CAS  Google Scholar 

  52. King KJ, Nicholson HD, Assinder SJ (2006) Effect of increasing ratio of estrogen:androgen on proliferation of normal human prostate stromal and epithelial cells, and the malignant cell line LNCaP. Prostate 66:105–114

    Article  PubMed  CAS  Google Scholar 

  53. Rajhans R, Nair S, Holden AH et al (2007) Oncogenic potential of the nuclear receptor coregulator proline-, glutamic acid-, leucine-rich protein 1/modulator of the nongenomic actions of the estrogen receptor. Cancer Res 67:5505–5512

    Article  PubMed  CAS  Google Scholar 

  54. Nair S, Vadlamudi RK (2007) Emerging significance of ER-coregulator PELP1/MNAR in cancer. Histol Histopathol 22:91–96

    PubMed  CAS  Google Scholar 

  55. Horard B, Vanacker J-M (2003) Estrogen receptor-related receptors: orphan receptors desperately seeking a ligand. J Mol Endocrinol 31:349–357

    Article  PubMed  CAS  Google Scholar 

  56. Cavallini A, Notarnicola M, Giannini P et al (2005) Oestrogen receptor-related receptor alpha (ERRa) and oestrogen receptors (ERa and ERb) exhibit different gene expression in human colorectal tumour progression. Eur J Cancer 41:1487–1494

    Article  PubMed  CAS  Google Scholar 

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We declare that we have no conflict of interest.

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Authors and Affiliations

  1. Department of Anatomy and Histology–Embryology, University of Patras, 26500, Rion, Greece

    Vassiliki Tzelepi, Zinovia Kefalopoulou, John N. Varakis & Georgia Sotiropoulou-Bonikou

  2. Department of Pathology, University of Patras, 26500, Rion, Greece

    Vassiliki Tzelepi & Zinovia Kefalopoulou

  3. Division of Oncology, Department of Internal Medicine, Medical School, University of Patras, 26500, Rion, Greece

    Petros Grivas & Haralabos Kalofonos

  4. Department of Internal Medicine, Hahnemann University Hospital/Drexel University College of Medicine, Philadelphia, PA, 19102, USA

    Petros Grivas

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  1. Vassiliki Tzelepi
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Correspondence to Georgia Sotiropoulou-Bonikou.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00428-008-0719-1

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Tzelepi, V., Grivas, P., Kefalopoulou, Z. et al. Expression of estrogen receptor co-regulators NCoR and PELP1 in epithelial cells and myofibroblasts of colorectal carcinomas: cytoplasmic translocation of NCoR in epithelial cells correlates with worse prognosis. Virchows Arch 454, 41–53 (2009). https://doi.org/10.1007/s00428-008-0708-4

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  • DOI: https://doi.org/10.1007/s00428-008-0708-4

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