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Estrogen receptor α/β, AIB1, and TIF2 in colorectal carcinogenesis: do coregulators have prognostic significance?

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Abstract

Purpose

Estrogen receptor β (ERβ) is abundantly expressed in colorectal tissue, but its role in colorectal carcinogenesis remains elusive. Estrogen receptor coregulators, amplified in breast cancer 1 (AIB1) and transcription intermediary factor 2 (TIF2), have been well-characterized, but their expression in colorectal carcinomas has not been investigated.

Materials and methods

Estrogen receptor α (ERα), ERβ, AIB1, and TIF2 protein expression were evaluated by immunohistochemistry in colorectal normal mucosa, adenomas, and adenocarcinomas from 110 patients with colorectal cancer.

Results

ERα expression was rare in colorectal tissue and its expression does not appear to be associated with colorectal carcinogenesis. ERβ, AIB1, and TIF2 were detected in the nucleus of epithelial, endothelial, inflammatory, smooth muscle cells, and myofibroblasts. The expression of the three proteins was significantly increased in epithelial cells of carcinomas compared to normal mucosa. In carcinomas, a significant correlation between the levels of expression of AIB1 and TIF2 was noted. Although AIB1 overexpression was associated with local tumor invasion, it was also found to correlate independently with prolonged overall survival.

Conclusions

ERβ, AIB1, and TIF2 appear to be involved in colorectal tumorigenesis and might have prognostic significance.

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References

  1. Fiorelli G, Picariello L, Martineti V, Tonelli F, Brandi ML (1999) Functional estrogen receptor beta in colon cancer cells. Biochem Biophys Res Commun 261:521–527

    Article  PubMed  CAS  Google Scholar 

  2. Konstantinopoulos PA, Kominea A, Vandoros G et al (2003) Oestrogen receptor beta (ERbeta) is abundantly expressed in normal colonic mucosa, but declines in colon adenocarcinoma paralleling the tumour’s dedifferentiation. Eur J Cancer 39:1251–1258

    Article  PubMed  CAS  Google Scholar 

  3. Moore JT, McKee DD, Slentz-Kesler K et al (1998) Cloning and characterization of human estrogen receptor beta isoforms. Biochem Biophys Res Commun 247:75–78

    Article  PubMed  CAS  Google Scholar 

  4. Cavallini A, Messa C, Pricci M, Caruso ML, Barone M, Di Leo A (2002) Distribution of estrogen receptor subtypes, expression of their variant forms, and clinicopathological characteristics of human colorectal cancer. Dig Dis Sci 47:2720–2728

    Article  PubMed  CAS  Google Scholar 

  5. Nilsson S, Makela S, Treuter E et al (2001) Mechanisms of estrogen action. Physiol Rev 81:1535–1565

    PubMed  CAS  Google Scholar 

  6. Jensen EV, Jordan VC (2003) The estrogen receptor: a model for molecular medicine. Clin Cancer Res 9:1980–1989

    PubMed  CAS  Google Scholar 

  7. Peng B, Lu B, Leygue E, Murphy LC (2003) Putative functional characteristics of human estrogen receptor-beta isoforms. J Mol Endocrinol 30:13–29

    Article  PubMed  CAS  Google Scholar 

  8. Acconcia F, Kumar R (2006) Signaling regulation of genomic and nongenomic functions of estrogen receptors. Cancer Lett 238:1–14

    Article  PubMed  CAS  Google Scholar 

  9. 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 

  10. Anzick SL, Kononen J, Walker RL et al (1997) AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277:965–968

    Article  PubMed  CAS  Google Scholar 

  11. Glaeser MT, Hanstein B, Beckmann MW, Niederacher D (2001) Gene amplification and expression of the steroid receptor coactivator SRC3 (AIB1) in sporadic breast and endometrial carcinomas. Horm Metab Res 33:121–126

    Article  PubMed  CAS  Google Scholar 

  12. Sakakura C, Hagiwara A, Yasuoka R et al (2000) Amplification and over-expression of the AIB1 nuclear receptor co-activator gene in primary gastric cancers. Int J Cancer 89:217–223

    Article  PubMed  CAS  Google Scholar 

  13. Wang Y, Wu MC, Sham JS, Zhang W, Wu WQ, Guan XY (2002) Prognostic significance of c-myc and AIB1 amplification in hepatocellular carcinoma. A broad survey using high-throughput tissue microarray. Cancer 95:2346–2352

    Article  PubMed  CAS  Google Scholar 

  14. Gnanapragasam VJ, Leung HY, Pulimood AS, Neal DE, Robson CN (2001) Expression of RAC 3, a steroid hormone receptor co-activator in prostate cancer. Br J Cancer 85:1928–1936

    Article  PubMed  CAS  Google Scholar 

  15. Torres-Arzayus MI, Font de Mora J, Yuan J et al (2004) High tumor incidence and activation of the PI3K/AKT pathway in transgenic mice define AIB1 as an oncogene. Cancer Cell 6:263–274

    Article  PubMed  CAS  Google Scholar 

  16. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428

    Article  PubMed  CAS  Google Scholar 

  17. Lund AH, van Lohuizen M (2004) Epigenetics and cancer. Genes Dev 18:2315–2335

    Article  PubMed  CAS  Google Scholar 

  18. Louie MC, Revenko AS, Zou JX, Yao J, Chen HW (2006) Direct control of cell cycle gene expression by proto-oncogene product ACTR, and its autoregulation underlies its transforming activity. Mol Cell Biol 26:3810–3823

    Article  PubMed  CAS  Google Scholar 

  19. Louie MC, Zou JX, Rabinovich A, Chen HW (2004) ACTR/AIB1 functions as an E2F1 coactivator to promote breast cancer cell proliferation and antiestrogen resistance. Mol Cell Biol 24:5157–5171

    Article  PubMed  CAS  Google Scholar 

  20. Voegel JJ, Heine MJ, Zechel C, Chambon P, Gronemeyer H (1996) TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J 15:3667–3675

    PubMed  CAS  Google Scholar 

  21. Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, Rosenfeld MG (1997) The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387:677–684

    Article  PubMed  CAS  Google Scholar 

  22. Giannini R, Cavallini A (2005) Expression analysis of a subset of coregulators and three nuclear receptors in human colorectal carcinoma. Anticancer Res 25:4287–4292

    PubMed  CAS  Google Scholar 

  23. Mukherjee A, Amato P, Allred DC et al (2006) Steroid receptor coactivator 2 is essential for progesterone-dependent uterine function and mammary morphogenesis: insights from the mouse—implications for the human. J Steroid Biochem Mol Biol 102:22–31

    Article  PubMed  CAS  Google Scholar 

  24. Picard F, Gehin M, Annicotte J et al (2002) SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell 111:931–941

    Article  PubMed  CAS  Google Scholar 

  25. Dunlop TW, Vaisanen S, Frank C, Carlberg C (2004) The genes of the coactivator TIF2 and the corepressor SMRT are primary 1alpha,25(OH)2D3 targets. J Steroid Biochem Mol Biol 89–90:257–260

    Article  PubMed  Google Scholar 

  26. Holt PR, Arber N, Halmos B et al (2002) Colonic epithelial cell proliferation decreases with increasing levels of serum 25-hydroxy vitamin D. Cancer Epidemiol Biomarkers Prev 11:113–119

    PubMed  CAS  Google Scholar 

  27. Duong BN, Elliott S, Frigo DE et al (2006) AKT regulation of estrogen receptor beta transcriptional activity in breast cancer. Cancer Res 66:8373–8381

    Article  PubMed  CAS  Google Scholar 

  28. Jassam N, Bell SM, Speirs V, Quirke P (2005) Loss of expression of oestrogen receptor beta in colon cancer and its association with Dukes’ staging. Oncol Rep 14:17–21

    PubMed  CAS  Google Scholar 

  29. Witte D, Chirala M, Younes A, Li Y, Younes M (2001) Estrogen receptor beta is expressed in human colorectal adenocarcinoma. Hum Pathol 32:940–944

    Article  PubMed  CAS  Google Scholar 

  30. Wong NA, Malcomson RD, Jodrell DI, Groome NP, Harrison DJ, Saunders PT (2005) ERbeta isoform expression in colorectal carcinoma: an in vivo and in vitro study of clinicopathological and molecular correlates. J Pathol 207:53–60

    Article  PubMed  CAS  Google Scholar 

  31. Secreto FJ, Monroe DG, Dutta S, Ingle JN, Spelsberg TC (2007) Estrogen receptor alpha/beta isoforms, but not betacx, modulate unique patterns of gene expression and cell proliferation in Hs578T cells. J Cell Biochem 101(5):1125–1147

    Article  PubMed  CAS  Google Scholar 

  32. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) REporting recommendations for tumor MARKer prognostic studies (REMARK). Nat Clin Pract Oncol 2:416–422

    Article  PubMed  CAS  Google Scholar 

  33. Singh S, Poulsom R, Hanby AM, Rogers LA, Wright NA, Sheppard MC, Langman MJ (1998) Expression of oestrogen receptor and oestrogen-inducible genes pS2 and ERD5 in large bowel mucosa and cancer. J Pathol 184(2):153–160

    Article  PubMed  CAS  Google Scholar 

  34. Cho NL, Redston N, Zauber AG et al (2008) Aberrant crypt foci in the adenoma prevention with celecoxib trial. Cancer Prev Res 1:21–31 doi:10.1158/1940-6207.CAPR-07-0011

    Article  Google Scholar 

  35. Foley EF, Jazaeri AA, Shupnik MA, Jazaeri O, Rice LW (2000) Selective loss of estrogen receptor beta in malignant human colon. Cancer Res 60:245–248

    PubMed  CAS  Google Scholar 

  36. Campbell-Thompson M, Lynch IJ, Bhardwaj B (2001) Expression of estrogen receptor (ER) subtypes and ERbeta isoforms in colon cancer. Cancer Res 61:632–640

    PubMed  CAS  Google Scholar 

  37. Cho NL, Javid SH, Carothers AM, Redston M, Bertagnolli MM (2007) Estrogen receptors alpha and beta are inhibitory modifiers of Apc-dependent tumorigenesis in the proximal colon of Min/ + mice. Cancer Res 67(5):2366–2372

    Article  PubMed  CAS  Google Scholar 

  38. Giroux V, Lemay F, Bernatchez G, Robitaille Y, Carrier JC (2008) Estrogen receptor beta deficiency enhances small intestinal tumorigenesis in ApcMin/+ mice. Int J Cancer 123(2):303–311

    Article  PubMed  CAS  Google Scholar 

  39. O’Neill PA, Davies MP, Shaaban AM, Innes H, Torevell A, Sibson DR, Foster CS (2004) Wild-type oestrogen receptor beta (ERbeta1) mRNA and protein expression in Tamoxifen-treated post-menopausal breast cancers. Br J Cancer 91(9):1694–1702

    PubMed  Google Scholar 

  40. Balfe PJ, McCann AH, Welch HM, Kerin MJ (2004) Estrogen receptor beta and breast cancer. Eur J Surg Oncol 30(10):1043–1050

    Article  PubMed  CAS  Google Scholar 

  41. 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 

  42. Narayan S, Rajakumar G, Prouix H, Singh P (1992) Estradiol is trophic for colon cancer in mice: effect on ornithine decarboxylase and c-myc messenger RNA. Gastroenterology 103:1823–1832

    PubMed  CAS  Google Scholar 

  43. Singh S, Paraskeva C, Gallimore PH, Sheppard MC, Langman MJ (1994) Differential growth response to oestrogen of premalignant and malignant colonic cell lines. Anticancer Res 14:1037–1041

    PubMed  CAS  Google Scholar 

  44. Winter DC, Taylor C, C O’Sullivan G, Harvey BJ (2000) Mitogenic effects of oestrogen mediated by a non-genomic receptor in human colon. Br J Surg 87:1684–1689

    Article  PubMed  CAS  Google Scholar 

  45. Arai N, Strom A, Rafter JJ, Gustafsson JA (2000) Estrogen receptor beta mRNA in colon cancer cells: growth effects of estrogen and genistein. Biochem Biophys Res Commun 270:425–431

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  47. Hennessy BA, Harvey BJ, Healy V (2005) 17beta-Estradiol rapidly stimulates c-fos expression via the MAPK pathway in T84 cells. Mol Cell Endocrinol 229:39–47

    Article  PubMed  CAS  Google Scholar 

  48. Wade CB, Robinson S, Shapiro RA, Dorsa DM (2001) Estrogen receptor (ER)alpha and ERbeta exhibit unique pharmacologic properties when coupled to activation of the mitogen-activated protein kinase pathway. Endocrinology 142:2336–2342

    Article  PubMed  CAS  Google Scholar 

  49. Oduwole OO, Isomaa VV, Nokelainen PA, Stenback F, Vihko PT (2002) Downregulation of estrogen-metabolizing 17 beta-hydroxysteroid dehydrogenase type 2 expression correlates inversely with Ki67 proliferation marker in colon-cancer development. Int J Cancer 97:1–6

    Article  PubMed  CAS  Google Scholar 

  50. English MA, Kane KF, Cruickshank N, Langman MJ, Stewart PM, Hewison M (1999) Loss of estrogen inactivation in colonic cancer. J Clin Endocrinol Metab 84:2080–2085

    Article  PubMed  CAS  Google Scholar 

  51. Guo JY, Li X, Browning JD et al (2004) Dietary soy isoflavones and estrone protect ovariectomized ERalphaKO and wild-type mice from carcinogen-induced colon cancer. J Nutr 134:179–182

    PubMed  CAS  Google Scholar 

  52. Hudelist G, Czerwenka K, Kubista E, Marton E, Pischinger K, Singer CF (2003) Expression of sex steroid receptors and their co-factors in normal and malignant breast tissue: AIB1 is a carcinoma-specific co-activator. Breast Cancer Res Treat 78:193–204

    Article  PubMed  CAS  Google Scholar 

  53. Balmer NN, Richer JK, Spoelstra NS, Torkko KC, Lyle PL, Singh M (2006) Steroid receptor coactivator AIB1 in endometrial carcinoma, hyperplasia and normal endometrium: correlation with clinicopathologic parameters and biomarkers. Mod Pathol 19:1593–1605

    Article  PubMed  CAS  Google Scholar 

  54. Xie D, Sham JS, Zeng WF et al (2005) Correlation of AIB1 overexpression with advanced clinical stage of human colorectal carcinoma. Hum Pathol 36:777–783

    Article  PubMed  CAS  Google Scholar 

  55. Henke RT, Haddad BR, Kim SE et al (2004) Overexpression of the nuclear receptor coactivator AIB1 (SRC-3) during progression of pancreatic adenocarcinoma. Clin Cancer Res 10:6134–6142

    Article  PubMed  CAS  Google Scholar 

  56. Avivar A, Garcia-Macias MC, Ascaso E, Herrera G, O’Connor JE, de Mora JF (2006) Moderate overexpression of AIB1 triggers pre-neoplastic changes in mammary epithelium. FEBS Lett 580:5222–5226

    Article  PubMed  CAS  Google Scholar 

  57. Zhou G, Hashimoto Y, Kwak I, Tsai SY Tsai MJ (2003) Role of the steroid receptor coactivator SRC-3 in cell growth. Mol Cell Biol 23:7742–7755

    Article  PubMed  CAS  Google Scholar 

  58. List HJ, Lauritsen KJ, Reiter R, Powers C, Wellstein A, Riegel AT (2001) Ribozyme targeting demonstrates that the nuclear receptor coactivator AIB1 is a rate-limiting factor for estrogen-dependent growth of human MCF-7 breast cancer cells. J Biol Chem 276:23763–23768

    Article  PubMed  CAS  Google Scholar 

  59. Zhou HJ, Yan J, Luo W et al (2005) SRC-3 is required for prostate cancer cell proliferation and survival. Cancer Res 65:7976–7983

    PubMed  CAS  Google Scholar 

  60. Kuang SQ, Liao L, Wang S, Medina D, O’Malley BW, Xu J (2005) Mice lacking the amplified in breast cancer 1/steroid receptor coactivator-3 are resistant to chemical carcinogen-induced mammary tumorigenesis. Cancer Res 65:7993–8002

    PubMed  CAS  Google Scholar 

  61. Xu FP, Xie D, Wen JM et al (2007) SRC-3/AIB1 protein and gene amplification levels in human esophageal squamous cell carcinomas. Cancer Lett 245:69–74

    Article  PubMed  CAS  Google Scholar 

  62. Zhang H, Stephens LC, Kumar R (2006) Metastasis tumor antigen family proteins during breast cancer progression and metastasis in a reliable mouse model for human breast cancer. Clin Cancer Res 12:1479–1486

    Article  PubMed  CAS  Google Scholar 

  63. Li LB, Louie MC, Chen HW, Zou JX (2008) Proto-oncogene ACTR/AIB1 promotes cancer cell invasion by up-regulating specific matrix metalloproteinase expression. Cancer Lett 261:64–73

    Article  PubMed  CAS  Google Scholar 

  64. Kirkegaard T, McGlynn LM, Campbell FM et al (2007) Amplified in breast cancer 1 in human epidermal growth factor receptor-positive tumors of tamoxifen-treated breast cancer patients. Clin Cancer Res 13:1405–1411

    Article  PubMed  CAS  Google Scholar 

  65. Luo JH, Xie D, Liu MZ et al (2008) Protein expression and amplification of AIB1 in human urothelial carcinoma of the bladder and overexpression of AIB1 is a new independent prognostic marker of patient survival. Int J Cancer 122:2554–2561

    Article  PubMed  CAS  Google Scholar 

  66. Coste A, Antal MC, Chan S, Kastner P, Mark M, O’Malley BW, Auwerx J (2006) Absence of the steroid receptor coactivator-3 induces B-cell lymphoma. EMBO J 25:2453–2464

    Article  PubMed  CAS  Google Scholar 

  67. Chen SL, Wang SC, Hosking B, Muscat GE (2001) Subcellular localization of the steroid receptor coactivators (SRCs) and MEF2 in muscle and rhabdomyosarcoma cells. Mol Endocrinol 15:783–796

    Article  PubMed  CAS  Google Scholar 

  68. Kurebayashi J, Otsuki T, Kunisue H, Tanaka K, Yamamoto S, Sonoo H (2000) Expression levels of estrogen receptor-alpha, estrogen receptor-beta, coactivators, and corepressors in breast cancer. Clin Cancer Res 6:512–518

    PubMed  CAS  Google Scholar 

  69. Yan J, Tsai SY, Tsai MJ (2006) SRC-3/AIB1: transcriptional coactivator in oncogenesis. Acta Pharmacol Sin 27:387–394

    Article  PubMed  Google Scholar 

  70. Yan J, Yu CT, Ozen M, Ittmann M, Tsai SY, Tsai MJ (2006) Steroid receptor coactivator-3 and activator protein-1 coordinately regulate the transcription of components of the insulin-like growth factor/AKT signaling pathway. Cancer Res 66:11039–11046

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We acknowledge the Committee of Research, University of Patras, Greece for the funding of our study. Study sponsors had no involvement in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.

Conflicts of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Division of Oncology and Clinical Oncology Laboratory, Medical School, University of Patras, 26504, Patras, Greece

    Petros D. Grivas & Haralabos Kalofonos

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

    Petros D. Grivas

  3. Department of Anatomy and Histology–Embryology, Medical School, University of Patras, 26504, Patras, Greece

    Vassiliki Tzelepi, Georgia Sotiropoulou-Bonikou & Zinovia Kefalopoulou

  4. Department of Pathology, Medical School, University of Patras, 26504, Patras, Greece

    Vassiliki Tzelepi

  5. Department of Biological Chemistry, Medical School, University of Athens, 11527, Athens, Greece

    Athanasios G. Papavassiliou

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  1. Petros D. Grivas
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Correspondence to Haralabos Kalofonos.

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Grivas, P.D., Tzelepi, V., Sotiropoulou-Bonikou, G. et al. Estrogen receptor α/β, AIB1, and TIF2 in colorectal carcinogenesis: do coregulators have prognostic significance?. Int J Colorectal Dis 24, 613–622 (2009). https://doi.org/10.1007/s00384-009-0647-9

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