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Breast Cancer Research and Treatment

, Volume 76, Issue 2, pp 167–173 | Cite as

Retinoid, Retinoic Acid Receptor β and Breast Cancer

  • Qifeng Yang
  • Takeo Sakurai
  • Kennichi Kakudo
Article

Abstract

Retinoids have been reported to inhibit the growth of several breast cancer cell lines in culture and to reduce breast tumor growth in animal models. Furthermore, retinoic acid (RA) can augment the action of other breast cancer cell growth inhibitors both in vitro and in vivo. Clinically, interest has increased in the potential use of retinoids for the prevention and treatment of human breast cancer. The regulation of cell growth and differentiation of normal, premalignant, and malignant cells by retinoids is mediated by the RA receptors (RARs) and retinoid X receptor. One of the target genes of retinoid receptors is RARβ2. A growing body of evidence supports the hypotheses that the RARβ2 gene is a tumor suppressor gene and the chemopreventive effects of retinoids are due to induction of RARβ2. RARβ2 expression is reduced in many malignant tumors including breast carcinoma. This paper will briefly discuss basic aspects of retinoids and retinoid acid receptor. In particular, we review what is now known for inactivation mechanism of RARβ2 and its role in tumor cell growth inhibition.

breast cancer demethylation hypermethylation loss of heterozygosity retinoid retinoid acid receptor 

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References

  1. 1.
    American Cancer Society: Cancer Facts and Figures. Amer-ican Cancer Society, Atlanta, GA, 1994Google Scholar
  2. 2.
    Harris JR, Lippman ME, Verounesi U, Willett W: Breast cancer. N Engl J Med 327: 319–328, 1992Google Scholar
  3. 3.
    Weston A, Harris CC: Chemical carcinogenesis. In: Holland JF, Frei E, Bast RC et al. (eds) Cancer Medicine. 4th edn, Vol 1, Williams and Wikins, Baltimore, MD, 1997, pp 261–276Google Scholar
  4. 4.
    Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N: Tamoxifen for prevention of breast cancer: report of the Na-tional Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371–1388, 1998Google Scholar
  5. 5.
    Sporn MB, Newton DL: Chemoprevention of cancer with retinoids. Fed Proc 38: 2528–2534, 1979Google Scholar
  6. 6.
    Hong WKI, Sporn MB: Recent advances in chemoprevention of cancer. Science 278: 1073–1077, 1997Google Scholar
  7. 7.
    Dragen KH, Rigas JR, Dmitrovsky E: The retinoids and cancer prevention mechanisms. The Oncologist 5: 361–368, 2000Google Scholar
  8. 8.
    Sporn MB, Roberts AB, Goodman DS: The Retinoids: Bi-ology, Chemistry, and Medicine. 2nd edn, Raven Press, New York, 1994Google Scholar
  9. 9.
    Hong WK, Lippman SM, Itri LM, Karp DD, Lee JS, Byers RM, Schantz SS, Kramer AM, Lotan R, Peters LL, Dimery IW, Brown BW, Goepfert H: Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 323: 795–801, 1990Google Scholar
  10. 10.
    Lippman SM, Lee JJ, Sabichi AL: Cancer chemoprevention: progress and promise. J Natl Cancer Inst 90: 1514–1528, 1998Google Scholar
  11. 11.
    Veronesi U, De Palo G, Marubini E, Costa A, Formelli F, Mariani L, Decensi A, Camerini T, Del Turco MR, Di Mauro MG, Muraca MG, DelVecchio M, Pinto C, D'Aiuto G, Boni C, Campa T, Magni A, Miceli R, Perloff M, Malone WF, Sporn MB: Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer. J Natl Cancer Inst 91: 1847–1856, 1999Google Scholar
  12. 12.
    Pfahl M: Vertebrate receptors: molecular biology, dimer-ization and response elements. Semin Cell Biol 5: 95–103, 1994Google Scholar
  13. 13.
    Mangelsdorf DJ, Evans RM: The RXR heterodimers and orphan receptors. Cell 83: 841–850, 1995Google Scholar
  14. 14.
    Chambon PA: Decade of molecular biology of retinoic acid receptors. FASEB J 10: 940–954, 1996Google Scholar
  15. 15.
    Li E: Structure and function of cytoplasmic retinoid binding proteins. Mol Cell Biochem 192: 105–108, 1999Google Scholar
  16. 16.
    Moon RC: Vitamin A, retinoids and breast cancer. Adv Exp Med Biol 364: 101–107, 1994Google Scholar
  17. 17.
    Lee PP, Lee MT, Darcy KM, Shudo K, Ip MM: Modulation of normal mammary epithelial cell proliferation, morphogen-esis, and functional differentiation by retinoids: a comparison of the retinobenzoic acid derivative RE80 with retinoic acid. Endocrinology 136: 1707–1717, 1995Google Scholar
  18. 18.
    Zhu WY, Jones CS, Kiss A, Matsukuma K, Amin S, De Luca LM: Retinoic acid inhibition of cell cycle progression in MCF-7 human breast cancer cells. Exp Cell Res 234: 293–299, 1997Google Scholar
  19. 19.
    Ng J-H, Nesaretnam K, Reimann K, Lai LC: Effect of ret-inoic acid and palm oil carotenoids on oestrone sulphatase and oestradiol-17β hydroxysteroid dehydrogenase activities in MCF-7 and MDA-MB-231 breast cancer cell lines. Int J Cancer 88: 135–138, 2000Google Scholar
  20. 20.
    Evans TRJ, Kaye SB: Retinoids: present role and future potential. Br J Cancer 80: 1–8, 1999Google Scholar
  21. 21.
    Wilcken NRC, Musgrove EA, Sutherland RL: Different points of action of retinoids and anti-estrogen in G1 phase identified in synchronized T-47D breast cancer cells. Int J Cancer 70: 291–296, 1997Google Scholar
  22. 22.
    Anzano MA, Byers SW, Smith JM, Peer CW, Mullen LT, Brown CC, Roberts AB, Sporn MB: Prevention of breast can-cer in the rat with 9-cis retinoid acid as a single agent and in combination with tamoxifen. Cancer Res 54: 4614–4617, 1994Google Scholar
  23. 23.
    Cobleigh MA, Dowlashahi K, Deutsch TA, Mehta RG, Moon RC, Minn F, Benson AD, Rademaker AW, Ashenhurst JB, Wade JL, Walter J: Phase I/II trial of tamoxifen with or without fenretinide, an analog of vitamin A, in women with metastatic breast cancer. J Clin Oncol 11: 474–477, 1993Google Scholar
  24. 24.
    Boccardo F, Canobbio L, Resasco M, Decensi AU, Pastorino G, Brema F: Phase II study of tamoxifen and high-dose retinyl acetate in patients with advanced breast cancer. J Cancer Res Clin Oncol 116: 503–506, 1990Google Scholar
  25. 25.
    Gottardis MM, Bischoff ED, Shirley MA, Wagoner MA, Lamph WW, Heyman RA: Chemoprevention of mammary carcinoma by LGD1069 (targretin): an RXR-selective ligand. Cancer Res 56: 5566–5570, 1996Google Scholar
  26. 26.
    Bischoff ED, Gottardis MM, Moon TE, Heyman RA, Lamph WW: Beyond tamoxifen: the retinoid X receptor-selective ligand LGD1069 (targretin) causes complete regression of mammary carcinoma. Cancer Res 58: 479–484, 1998Google Scholar
  27. 27.
    Bischoff ED, Heyman RA, Lamph WW: Effect of the retinoid X receptor-selective ligand LGD1069 on mammary carcinoma after tamoxifen failure. J Natl Cancer Inst 91: 2118, 1999Google Scholar
  28. 28.
    Wu Q, Dawson MI, Zheng Y, Hobbs PD, Agadir A, Jong L, Li Y, Liu R, Lin B, Zhang XK: Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids. Mol Cell Biol 17: 6598–6608, 1997.Google Scholar
  29. 29.
    Nason-Burchenal K, Dmitrovsky E: Retinoic acid, its re-arranged receptor, and acute promyelocytic leukemia. In: Bertino JR (ed) Encyclopedia of Cancer. Vol II, Academic Press, New York, NY, 1997, pp 1547–1560Google Scholar
  30. 30.
    Jing Y, Zhang J, Bleiweiss IJ, Waxman S, Zelent A, Mira-Lopez R: Defective expression of cellular retinal binding protein type I and retinoic acid receptors á 2, β2, ã 2 in human breast cancer cells. FASEB J 10: 1064–1070, 1996Google Scholar
  31. 31.
    Kuppumbatti YS, Bleiweiss IJ, Mandeli JP, Waxman S, Mira-y-Lopez R: Cellular retinol-binding protein expression and breast cancer. J Natl Cancer Inst 92: 475–480, 2000Google Scholar
  32. 32.
    Picard E, Seguin C, Monhoven N, Rochette-Egly C, Siat J, Borrelly J, Martinet Y, Martinet N, Vignaud JM: Expression of retinoid receptor genes and proteins in non-small-lung cancer. J Natl Cancer Inst 91: 1059–1066, 1999Google Scholar
  33. 33.
    Xu X-C, Liu X, Tahara E, Lippman SM, Lotan R: Expression and up-regulation of retinoic acid receptor-â is associated with retinoid sensitivity and colony formation in esophageal cancer cell lines. Cancer Res 59: 2477–2483, 1999Google Scholar
  34. 34.
    Xu X-C, Sneige N, Liu X, Nandagiri R, Lee JJ, Lukmanji F, Hortobagyi G, Lippman SM, Dhingra K, Lotan R: Progressive decrease in nuclear retinoic acid receptor β messenger RNA level during breast carcinogenesis. Cancer Res 57: 4992–4996, 1997Google Scholar
  35. 35.
    Widschwendter M, Berger J, Daxenbichler G, Muller-Holzner E, Widschwendter A, Mayr A, Marth C, Zeimet AG: Loss of retinoic acid receptor β expression in breast cancer and morphologically normal adjacent tissue but not in the nor-mal breast tissue distant from the cancer. Cancer Res 57: 4158–4161, 1997Google Scholar
  36. 36.
    Liu Y, Lee MO, Wang HG, Li Y, Hashimoto Y, Klaus M, Reed JC, Zhang X: Retinoic acid receptor â mediates the growth-inhibitory effect of retinoic acid by promoting ap-optosis in human breast cancer cells. Mol Cell Biol 16: 1138–1149, 1996Google Scholar
  37. 37.
    Lotan R, Xu XC, Lippman SM, Ro JY, Lee JS, Lee JJ, Hong WK: Suppression of retinoic acid receptor â in premalignant oral lesions and its up-regulation by isotretinoin. N Engl J Med 332: 1405–1410, 1995Google Scholar
  38. 38.
    Sun SY, Wan H, Yue P, Hong WK, Lotan R: Evidence that ret-inoic acid receptor β induction by retinoids is important for tu-mor cell growth inhibition. J Biol Chem 275: 17,149–17,153, 2000Google Scholar
  39. 39.
    De The'H, del MarVivanco-Ruiz M, Tiollais P, Stunnenberg HG, Dejan A: Identification of a retinoic acid responsive ele-ment in the retinoic acid receptor beta gene. Nature 343: 177–180, 1990Google Scholar
  40. 40.
    Valcarel R, Holz H, Garcia Jimenez C, Barettino D, Stunnenberg HG: Retinoid-dependent in vitro transcription mediated by the RXR/RAR heterodimer. Genes Dev 8: 3068–3079, 1994Google Scholar
  41. 41.
    Yang Q, Mori I, Shan L, Nakamura M, Nakamura Y, Utsunomiya H, Yoshimura G, Suzuma T, Tamaki T, Umemura T, Sakurai T, Kakudo K: Biallelic inactivation of retinoic acid receptor β2 gene by epigenetic change in breast cancer. Am J Pathol 158: 299–303, 2001Google Scholar
  42. 42.
    Bartsch D, Boye B, Baust C, zur Hausen H, Schwarz E: Retinoic acid-mediated repression of human papillomavirus 18 transcription and different ligand regulation of the retinoic acid receptor beta gene in non-tumorigenic and tumorigenic HeLa hybrid cells. EMBO J 11: 2283–2291, 1992Google Scholar
  43. 43.
    Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS: Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 274: 2057–2059, 1996Google Scholar
  44. 44.
    Yang Q, Yoshimura G, Sakurai T, Nakamura M, Nakamura Y, Shan L, Suzuma T, Takashi Y, Umemura T, Mori I, Kakudo K: Allelic loss of chromosome 3p24 correlates with tumor progression rather than with retinoic acid receptor β2 expres-sion in breast carcinoma. Breast Cancer Res Treat 70: 39–45, 2001Google Scholar
  45. 45.
    Bix M, Locksley RM: Independent and epigenetic regulation of the interleukin-4 alleles in CD4+T cells. Science 281: 1352–1354, 1998Google Scholar
  46. 46.
    Hollander GA, Zuklya S, Morel C, Mizoguchi E, Mobisson K, Simpson S, Terhorst C, Wishart W, Golan DE, Bhan AK, Burakoff SJ: Monoallelic expression of the interleukin-2 locus. Science 279: 2118–2121, 1998Google Scholar
  47. 47.
    Qiu H, Lotan R, Lippman SM, Xu X-C: Lack of correla-tion between expression of retinoic acid receptor-beta and loss of heterozygosity on chromosome band 3p24 in eso-phageal cancer. Genes Chromosomes Cancer 28: 196–202, 2000Google Scholar
  48. 48.
    Cote S, Sinnett D, Momparler RL: Demethylation by 5-aza-2-deoxycytidine of specific 5-methylcytosine sites in the promoter region of the retinoic acid receptor β gene in human colon carcinoma cells. Anticancer Drugs 9: 743–750, 1998Google Scholar
  49. 49.
    Sirchia SM, Ferguson AT, Sironi E, Subramanyan S, Orlandi R, Sukumar S, Sacchi N: Evidence of epigenetic changes af-fecting the chromatin state of the retinoic acid receptor β2 promoter in breast cancer cells. Oncogene 19: 1556–1563, 2000Google Scholar
  50. 50.
    Widschwendter M, Berger J, Hermann M, Muller HM, Amberger A, Zeschnigk M, Widschwendter A, Abendstein B, Zeimet AG, Daxenbichler G, Marth C: Methylation and silen-cing of the retinoic acid receptor β2 gene in breast cancer. J Natl Cancer Inst 92: 826–832, 2000Google Scholar
  51. 51.
    Arapshian A, Kuppumbatti YS, Mira-y-Lopez R: Methyla-tion of conserved CpG site neighboring the beta retinoic acid response element may mediate retinoic acid receptor beta gene silencing in MCF-7 breast cancer cells. Oncogene 19: 4066–4070, 2000Google Scholar
  52. 52.
    Yang Q, Sakurai T, Yoshimura G, Mori I, Nakamura M, Nakamura Y, Suzuma T, Tamaki T, Umemura T, Kakudo K: Hypermethylation does not account for the frequent loss of the retinoic acid receptor β2 in breast carcinoma. Anticancer Res 21: 1829–1833, 2001Google Scholar
  53. 53.
    Kinzler K, Vogelstein B: Lessons from hereditary colorectal cancer. Cell 87: 159–170, 1996Google Scholar
  54. 54.
    Zou CP, Youssef EM, Zou CC, Carey TE, Lotan R: Differential effects of chromosome 3p deletion on the expression of the putative tumor suppressor RARβ and on retinoid resistance in human squamous carcinoma cells. Oncogene 20: 6820–6827, 2001Google Scholar
  55. 55.
    Kato S, Mano H, Kumazwa T, Yoshizuwa Y, Kojima R, Masushige S: Effect of retinoid status on alpha, beta and gamma retinoic acid receptor mRNA levels in various rat tissues. Biochem J 286: 755–760, 1992Google Scholar
  56. 56.
    Verma AK, Schoemaker A, Simsimm R, Denning M, Zachman RD: Expression of retinoic acid nuclear receptors and tissue transglutaminase is altered in various tissues of rats fed 1 vitamin A-deficient diet. J Nutr 122: 2144–2152, 1992Google Scholar
  57. 57.
    Lin B, Chen GQ, Xiao D, Kolluri SK, Cao X, Su H, Zhang XK: Orphan receptor COUP-TF is required for in-duction of retinoic acid receptor beta, growth inhibition, and apoptosis by retinoic acid in cancer cells. Mol Cell Biol 20: 957–970, 2000.Google Scholar
  58. 58.
    Napoli JL: Interactions of retinoid binding proteins and en-zymes in retinoid metabolism. Biochim Biophys Acta 1440: 139–162, 1999Google Scholar
  59. 59.
    Spinella MJ, Freemantle SJ, Sekula D, Chang JH, Christie AJ, Dmitrovsky E: Retinoic acid promotes ubiquitination and pro-teolysis of cyclin D1 during induced tumor cell differentiation. J Biol Chem 274: 22,013–22,018, 1999Google Scholar
  60. 60.
    Langenfeld J, Kiyokawa H, Sekula D, Boyle J, Dmitrovsky E: Posttranslational regulation of cyclin D1 by retinoic acid: a chemoprevention mechanism. Proc Natl Acad Sci USA 94: 12,070–12,074, 1997Google Scholar
  61. 61.
    Spinella MJ, Dmitrovsky E: Aberrant retinoid signaling and breast cancer: the view from outside the nucleus. J Natl Cancer Inst 92: 438–440, 2000Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Qifeng Yang
    • 1
    • 2
    • 3
  • Takeo Sakurai
    • 3
  • Kennichi Kakudo
    • 2
  1. 1.Department of General Surgery, Qilu HospitalShandong UniversityJi'nanPeople's Republic of China
  2. 2.Second Department of PathologyWakayama Medical University School of MedicineWakayama CityJapan
  3. 3.Department of Surgery, Affiliated Kihoku HospitalWakayama Medical University School of MedicineKaturagi-cho, WakayamaJapan

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