Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/20332
標題: 雌性激素受體陰性乳癌細胞中探討Her2對於AR的基因表現與調控
Her2 is important to androgen receptor expression and phosphorylation in estrogen receptor negative breast cancer cells
作者: 黃振權
Huang, Chen-Chuan
關鍵字: 雌性激素;Estrogen receptor (ER);雄性激素;人類表皮因子受體;三陰性乳癌;Androgen receptor (AR);Human epidermal growth factor receptor-2 (Her2);Triple-negative breast cancer (TNBC)
出版社: 生命科學系所
引用: 1. Loibl S, et al. (2011) Androgen receptor expression in primary breast cancer and its predictive and prognostic value in patients treated with neoadjuvant chemotherapy. (Translated from eng) Breast Cancer Res Treat 130(2):477-487 (in eng). 2. Hu R, et al. (2011) Androgen receptor expression and breast cancer survival in postmenopausal women. (Translated from eng) Clin Cancer Res 17(7):1867-1874 (in eng). 3. Siegel R, Naishadham D, & Jemal A (2012) Cancer statistics, 2012. (Translated from eng) CA Cancer J Clin 62(1):10-29 (in eng). 4. Barnes NL, Ooi JL, Yarnold JR, & Bundred NJ (2012) Ductal carcinoma in situ of the breast. (Translated from eng) BMJ 344:e797 (in eng). 5. Haagensen CD, Lane N, Lattes R, & Bodian C (1978) Lobular neoplasia (so-called lobular carcinoma in situ) of the breast. (Translated from eng) Cancer 42(2):737-769 (in eng). 6. Hussain M & Cunnick GH (2011) Management of lobular carcinoma in-situ and atypical lobular hyperplasia of the breast--a review. (Translated from eng) Eur J Surg Oncol 37(4):279-289 (in eng). 7. Miki Y, Suzuki T, & Sasano H (2009) Intracrinology of sex steroids in ductal carcinoma in situ (DCIS) of human breast: comparison to invasive ductal carcinoma (IDC) and non-neoplastic breast. (Translated from eng) J Steroid Biochem Mol Biol 114(1-2):68-71 (in eng). 8. Bocker W (2002) [WHO classification of breast tumors and tumors of the female genital organs: pathology and genetics]. (Translated from ger) Verh Dtsch Ges Pathol 86:116-119 (in ger). 9. Hanby AM & Hughes TA (2008) In situ and invasive lobular neoplasia of the breast. (Translated from eng) Histopathology 52(1):58-66 (in eng). 10. Le-Petross H, Uppendahl L, & Stafford J (2011) Sonographic features of inflammatory breast cancer. (Translated from eng) Semin Roentgenol 46(4):275-279 (in eng). 11. Sorlie T, et al. (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. (Translated from eng) Proc Natl Acad Sci U S A 98(19):10869-10874 (in eng). 12. Sims AH, Howell A, Howell SJ, & Clarke RB (2007) Origins of breast cancer subtypes and therapeutic implications. (Translated from eng) Nat Clin Pract Oncol 4(9):516-525 (in eng). 13. Guttilla IK, Adams BD, & White BA (2012) ERalpha, microRNAs, and the epithelial-mesenchymal transition in breast cancer. (Translated from eng) Trends Endocrinol Metab 23(2):73-82 (in eng). 14. Thakkar JP & Mehta DG (2011) A review of an unfavorable subset of breast cancer: estrogen receptor positive progesterone receptor negative. (Translated from eng) Oncologist 16(3):276-285 (in eng). 15. Slamon DJ, et al. (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. (Translated from eng) Science 235(4785):177-182 (in eng). 16. Slamon DJ, et al. (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. (Translated from eng) Science 244(4905):707-712 (in eng). 17. De Laurentiis M, et al. (2010) Treatment of triple negative breast cancer (TNBC): current options and future perspectives. (Translated from eng) Cancer Treat Rev 36 Suppl 3:S80-86 (in eng). 18. Anders CK & Carey LA (2009) Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. (Translated from eng) Clin Breast Cancer 9 Suppl 2:S73-81 (in eng). 19. Couse JF & Korach KS (1999) Estrogen receptor null mice: what have we learned and where will they lead us? (Translated from eng) Endocr Rev 20(3):358-417 (in eng). 20. MacGregor JI & Jordan VC (1998) Basic guide to the mechanisms of antiestrogen action. (Translated from eng) Pharmacol Rev 50(2):151-196 (in eng). 21. Gruber CJ, Tschugguel W, Schneeberger C, & Huber JC (2002) Production and actions of estrogens. (Translated from eng) N Engl J Med 346(5):340-352 (in eng). 22. Burns KA & Korach KS (2012) Estrogen receptors and human disease: an update. (Translated from Eng) Arch Toxicol (in Eng). 23. Brandenberger AW, Tee MK, & Jaffe RB (1998) Estrogen receptor alpha (ER-alpha) and beta (ER-beta) mRNAs in normal ovary, ovarian serous cystadenocarcinoma and ovarian cancer cell lines: down-regulation of ER-beta in neoplastic tissues. (Translated from eng) J Clin Endocrinol Metab 83(3):1025-1028 (in eng). 24. Castiglione F, et al. (2008) Expression of estrogen receptor beta in colon cancer progression. (Translated from eng) Diagn Mol Pathol 17(4):231-236 (in eng). 25. Edvardsson K, Strom A, Jonsson P, Gustafsson JA, & Williams C (2011) Estrogen receptor beta induces antiinflammatory and antitumorigenic networks in colon cancer cells. (Translated from eng) Mol Endocrinol 25(6):969-979 (in eng). 26. Kawashima H & Nakatani T (2012) Involvement of estrogen receptors in prostatic diseases. (Translated from eng) Int J Urol 19(6):512-522 (in eng). 27. Pandini G, et al. (2007) 17beta-estradiol up-regulates the insulin-like growth factor receptor through a nongenotropic pathway in prostate cancer cells. (Translated from eng) Cancer Res 67(18):8932-8941 (in eng). 28. Jongen V, et al. (2009) Expression of estrogen receptor-alpha and -beta and progesterone receptor-A and -B in a large cohort of patients with endometrioid endometrial cancer. (Translated from eng) Gynecol Oncol 112(3):537-542 (in eng). 29. Manole D, Schildknecht B, Gosnell B, Adams E, & Derwahl M (2001) Estrogen promotes growth of human thyroid tumor cells by different molecular mechanisms. (Translated from eng) J Clin Endocrinol Metab 86(3):1072-1077 (in eng). 30. Yue W, et al. (2005) Tamoxifen versus aromatase inhibitors for breast cancer prevention. (Translated from eng) Clin Cancer Res 11(2 Pt 2):925s-930s (in eng). 31. Deroo BJ & Korach KS (2006) Estrogen receptors and human disease. (Translated from eng) J Clin Invest 116(3):561-570 (in eng). 32. Evans RM (1988) The steroid and thyroid hormone receptor superfamily. (Translated from eng) Science 240(4854):889-895 (in eng). 33. Kumar R & Thompson EB (1999) The structure of the nuclear hormone receptors. (Translated from eng) Steroids 64(5):310-319 (in eng). 34. Lannigan DA (2003) Estrogen receptor phosphorylation. (Translated from eng) Steroids 68(1):1-9 (in eng). 35. Pearce ST & Jordan VC (2004) The biological role of estrogen receptors alpha and beta in cancer. (Translated from eng) Crit Rev Oncol Hematol 50(1):3-22 (in eng). 36. Acconcia F & Kumar R (2006) Signaling regulation of genomic and nongenomic functions of estrogen receptors. (Translated from eng) Cancer Lett 238(1):1-14 (in eng). 37. Leclercq G (2002) Molecular forms of the estrogen receptor in breast cancer. (Translated from eng) J Steroid Biochem Mol Biol 80(3):259-272 (in eng). 38. Hall JM, Couse JF, & Korach KS (2001) The multifaceted mechanisms of estradiol and estrogen receptor signaling. (Translated from eng) J Biol Chem 276(40):36869-36872 (in eng). 39. McKenna NJ, et al. (1999) Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions. (Translated from eng) J Steroid Biochem Mol Biol 69(1-6):3-12 (in eng). 40. Smith CL, Nawaz Z, & O''Malley BW (1997) Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. (Translated from eng) Mol Endocrinol 11(6):657-666 (in eng). 41. Curtis SW, et al. (1996) Physiological coupling of growth factor and steroid receptor signaling pathways: estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor. (Translated from eng) Proc Natl Acad Sci U S A 93(22):12626-12630 (in eng). 42. Font de Mora J & Brown M (2000) AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. (Translated from eng) Mol Cell Biol 20(14):5041-5047 (in eng). 43. Rowan BG, Weigel NL, & O''Malley BW (2000) Phosphorylation of steroid receptor coactivator-1. Identification of the phosphorylation sites and phosphorylation through the mitogen-activated protein kinase pathway. (Translated from eng) J Biol Chem 275(6):4475-4483 (in eng). 44. Kato S (2001) Estrogen receptor-mediated cross-talk with growth factor signaling pathways. (Translated from eng) Breast Cancer 8(1):3-9 (in eng). 45. Kushner PJ, et al. (2000) Estrogen receptor pathways to AP-1. (Translated from eng) J Steroid Biochem Mol Biol 74(5):311-317 (in eng). 46. Mendelsohn ME (2000) Nongenomic, ER-mediated activation of endothelial nitric oxide synthase: how does it work? What does it mean? (Translated from eng) Circ Res 87(11):956-960 (in eng). 47. Mendelsohn ME (2000) Mechanisms of estrogen action in the cardiovascular system. (Translated from eng) J Steroid Biochem Mol Biol 74(5):337-343 (in eng). 48. Simoncini T, et al. (2000) Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. (Translated from eng) Nature 407(6803):538-541 (in eng). 49. Kousteni S, et al. (2001) Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. (Translated from eng) Cell 104(5):719-730 (in eng). 50. Brisken C & O''Malley B (2010) Hormone action in the mammary gland. (Translated from eng) Cold Spring Harb Perspect Biol 2(12):a003178 (in eng). 51. Stingl J (2011) Estrogen and progesterone in normal mammary gland development and in cancer. (Translated from eng) Horm Cancer 2(2):85-90 (in eng). 52. Parl FF, Schmidt BP, Dupont WD, & Wagner RK (1984) Prognostic significance of estrogen receptor status in breast cancer in relation to tumor stage, axillary node metastasis, and histopathologic grading. (Translated from eng) Cancer 54(10):2237-2242 (in eng). 53. Hong Y & Chen S (2006) Aromatase inhibitors: structural features and biochemical characterization. (Translated from eng) Ann N Y Acad Sci 1089:237-251 (in eng). 54. Henderson IC & Piccart-Gebhart MJ (2005) The evolving role of aromatase inhibitors in adjuvant breast cancer therapy. (Translated from eng) Clin Breast Cancer 6(3):206-215 (in eng). 55. Jelovac D, Macedo L, Goloubeva OG, Handratta V, & Brodie AM (2005) Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model. (Translated from eng) Cancer Res 65(12):5439-5444 (in eng). 56. Long BJ, Jelovac D, Thiantanawat A, & Brodie AM (2002) The effect of second-line antiestrogen therapy on breast tumor growth after first-line treatment with the aromatase inhibitor letrozole: long-term studies using the intratumoral aromatase postmenopausal breast cancer model. (Translated from eng) Clin Cancer Res 8(7):2378-2388 (in eng). 57. Veronesi U, et al. (1998) Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. (Translated from eng) Lancet 352(9122):93-97 (in eng). 58. Fisher B, et al. (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. (Translated from eng) J Natl Cancer Inst 90(18):1371-1388 (in eng). 59. Waters EA, McNeel TS, Stevens WM, & Freedman AN (2012) Use of tamoxifen and raloxifene for breast cancer chemoprevention in 2010. (Translated from Eng) Breast Cancer Res Treat (in Eng). 60. Roskoski R, Jr. (2004) The ErbB/HER receptor protein-tyrosine kinases and cancer. (Translated from eng) Biochem Biophys Res Commun 319(1):1-11 (in eng). 61. Marmor MD, Skaria KB, & Yarden Y (2004) Signal transduction and oncogenesis by ErbB/HER receptors. (Translated from eng) Int J Radiat Oncol Biol Phys 58(3):903-913 (in eng). 62. Graus-Porta D, Beerli RR, Daly JM, & Hynes NE (1997) ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. (Translated from eng) EMBO J 16(7):1647-1655 (in eng). 63. Rowinsky EK (2003) Signal events: Cell signal transduction and its inhibition in cancer. (Translated from eng) Oncologist 8 Suppl 3:5-17 (in eng). 64. da Cunha Santos G, Shepherd FA, & Tsao MS (2011) EGFR mutations and lung cancer. (Translated from eng) Annu Rev Pathol 6:49-69 (in eng). 65. Zaczek A, Brandt B, & Bielawski KP (2005) The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches. (Translated from eng) Histol Histopathol 20(3):1005-1015 (in eng). 66. Prigent SA & Gullick WJ (1994) Identification of c-erbB-3 binding sites for phosphatidylinositol 3''-kinase and SHC using an EGF receptor/c-erbB-3 chimera. (Translated from eng) EMBO J 13(12):2831-2841 (in eng). 67. Normanno N, et al. (2005) Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in breast cancer: current status and future development. (Translated from eng) Front Biosci 10:2611-2617 (in eng). 68. Meyer D & Birchmeier C (1995) Multiple essential functions of neuregulin in development. (Translated from eng) Nature 378(6555):386-390 (in eng). 69. Eccles SA (2011) The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology. (Translated from eng) Int J Dev Biol 55(7-9):685-696 (in eng). 70. DiAugustine RP, Richards RG, & Sebastian J (1997) EGF-related peptides and their receptors in mammary gland development. (Translated from eng) J Mammary Gland Biol Neoplasia 2(2):109-117 (in eng). 71. Normanno N & Ciardiello F (1997) EGF-related peptides in the pathophysiology of the mammary gland. (Translated from eng) J Mammary Gland Biol Neoplasia 2(2):143-151 (in eng). 72. Rubin I & Yarden Y (2001) The basic biology of HER2. (Translated from eng) Ann Oncol 12 Suppl 1:S3-8 (in eng). 73. Yarden Y (2001) Biology of HER2 and its importance in breast cancer. (Translated from eng) Oncology 61 Suppl 2:1-13 (in eng). 74. Ross JS & Fletcher JA (1998) The HER-2/neu Oncogene in Breast Cancer: Prognostic Factor, Predictive Factor, and Target for Therapy. (Translated from Eng) Oncologist 3(4):237-252 (in Eng). 75. Tabernero J, Macarulla T, Ramos FJ, & Baselga J (2005) Novel targeted therapies in the treatment of gastric and esophageal cancer. (Translated from eng) Ann Oncol 16(11):1740-1748 (in eng). 76. Ngeow J, Tan IB, & Choo SP (2011) Targeted therapies in the treatment of gastric cancer. (Translated from eng) Asia Pac J Clin Oncol 7(3):224-235 (in eng). 77. Yoong J, Michael M, & Leong T (2011) Targeted therapies for gastric cancer: current status. (Translated from eng) Drugs 71(11):1367-1384 (in eng). 78. Arteaga CL, et al. (2012) Treatment of HER2-positive breast cancer: current status and future perspectives. (Translated from eng) Nat Rev Clin Oncol 9(1):16-32 (in eng). 79. Fang L, Barekati Z, Zhang B, Liu Z, & Zhong X (2011) Targeted therapy in breast cancer: what''s new? (Translated from eng) Swiss Med Wkly 141:w13231 (in eng). 80. Sachdev JC & Jahanzeb M (2012) Blockade of the HER family of receptors in the treatment of HER2-positive metastatic breast cancer. (Translated from eng) Clin Breast Cancer 12(1):19-29 (in eng). 81. Ismail-Khan R & Bui MM (2010) A review of triple-negative breast cancer. (Translated from eng) Cancer Control 17(3):173-176 (in eng). 82. Gelmon K, et al. (2012) Targeting triple-negative breast cancer: optimising therapeutic outcomes. (Translated from Eng) Ann Oncol (in Eng). 83. Gelmann EP (2002) Molecular biology of the androgen receptor. (Translated from eng) J Clin Oncol 20(13):3001-3015 (in eng). 84. Feldman BJ & Feldman D (2001) The development of androgen-independent prostate cancer. (Translated from eng) Nat Rev Cancer 1(1):34-45 (in eng). 85. Anbalagan M, Huderson B, Murphy L, & Rowan BG (2012) Post-translational modifications of nuclear receptors and human disease. (Translated from eng) Nucl Recept Signal 10:e001 (in eng). 86. Hsu FN, et al. (2011) Regulation of androgen receptor and prostate cancer growth by cyclin-dependent kinase 5. (Translated from eng) J Biol Chem 286(38):33141-33149 (in eng). 87. Gioeli D, et al. (2002) Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. (Translated from eng) J Biol Chem 277(32):29304-29314 (in eng). 88. Zhou ZX, Kemppainen JA, & Wilson EM (1995) Identification of three proline-directed phosphorylation sites in the human androgen receptor. (Translated from eng) Mol Endocrinol 9(5):605-615 (in eng). 89. Hsu FN, Yang MS, Lin E, Tseng CF, & Lin H (2011) The significance of Her2 on androgen receptor protein stability in the transition of androgen requirement in prostate cancer cells. (Translated from eng) Am J Physiol Endocrinol Metab 300(5):E902-908 (in eng). 90. He J, et al. (2012) Prognostic value of androgen receptor expression in operable triple-negative breast cancer: a retrospective analysis based on a tissue microarray. (Translated from eng) Med Oncol 29(2):406-410 (in eng). 91. Brys M (2000) Androgens and androgen receptor: do they play a role in breast cancer? (Translated from eng) Med Sci Monit 6(2):433-438 (in eng). 92. Liao DJ & Dickson RB (2002) Roles of androgens in the development, growth, and carcinogenesis of the mammary gland. (Translated from eng) J Steroid Biochem Mol Biol 80(2):175-189 (in eng). 93. Gucalp A & Traina TA (2010) Triple-negative breast cancer: role of the androgen receptor. (Translated from eng) Cancer J 16(1):62-65 (in eng). 94. Nahleh Z (2008) Androgen receptor as a target for the treatment of hormone receptor-negative breast cancer: an unchartered territory. (Translated from eng) Future Oncol 4(1):15-21 (in eng). 95. Nicolas Diaz-Chico B, et al. (2007) Androgens and androgen receptors in breast cancer. (Translated from eng) J Steroid Biochem Mol Biol 105(1-5):1-15 (in eng). 96. Peters AA, et al. (2009) Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. (Translated from eng) Cancer Res 69(15):6131-6140 (in eng). 97. Wang Y, et al. (2011) Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers. (Translated from eng) Oncogene 30(42):4327-4338 (in eng). 98. Salah Z, Maoz M, Pizov G, & Bar-Shavit R (2007) Transcriptional regulation of human protease-activated receptor 1: a role for the early growth response-1 protein in prostate cancer. (Translated from eng) Cancer Res 67(20):9835-9843 (in eng). 99. Hoffmann E, et al. (2008) Transcriptional regulation of EGR-1 by the interleukin-1-JNK-MKK7-c-Jun pathway. (Translated from eng) J Biol Chem 283(18):12120-12128 (in eng). 100. Kuo PL, Chen YH, Chen TC, Shen KH, & Hsu YL (2011) CXCL5/ENA78 increased cell migration and epithelial-to-mesenchymal transition of hormone-independent prostate cancer by early growth response-1/snail signaling pathway. (Translated from eng) J Cell Physiol 226(5):1224-1231 (in eng). 101. Baron V, Duss S, Rhim J, & Mercola D (2003) Antisense to the early growth response-1 gene (Egr-1) inhibits prostate tumor development in TRAMP mice. (Translated from eng) Ann N Y Acad Sci 1002:197-216 (in eng). 102. Lemieux E, et al. (2009) Constitutively active MEK1 is sufficient to induce epithelial-to-mesenchymal transition in intestinal epithelial cells and to promote tumor invasion and metastasis. (Translated from eng) Int J Cancer 125(7):1575-1586 (in eng).
摘要: 
根據行政院衛生署的統計,乳癌為台灣女性好發癌症排名第一位,因此對於乳癌的發生原因以及相關機制的探討成為一個重要的課題。對於癌症治療有許多方法,除了傳統的手術切除及化療之外,標靶治療成為近年來一個新興手段。透過研究了解乳癌細胞在分子生物方面的訊息傳遞路徑,對於標靶治療目標選擇顯得格外重要。在臨床的應用上,Estrogen receptor (ER)、Progesterone Receptor (PR)、Human epidermal growth factor receptor-2 (Her2)為三種常用的分子標誌,研究最為透徹,許多乳癌標靶藥物設計方向,也以拮抗這三種受體為主,例如Tamoxifen (anti-ER)以及Herceptin (anti-Her2)。但是約有12%-20%的乳癌患者,ER、PR、Her2表現皆為陰性,這類病人不僅預後差,腫瘤的惡性程度高並且容易轉移,因此尋找新的分子標靶成為熱門的研究主題。在近年來的研究中,Androgen receptor(AR)被認為是有潛力的乳癌治療標靶對象,不僅從病人的病理組織切片中可以看到AR有過度表現的現象(1),AR的表現與否也與病人的存活率有相關性(2)。承襲本實驗室對於AR的了解,探討AR在乳癌中如何被調控。本研究中發現,在AR受到R1881的活化刺激之後,隨著R1881處理的時間越長,會使得MDA-MB-453細胞株 (ER陰性乳癌細胞)的生長受到抑制,進一步分析蛋白表現則發現Egr-1表現量降低且p27表現量增加。AR可能透過增加p27蛋白基因表現使細胞週期受到抑制而導致癌細胞生長趨緩。AR的上游可被Her2所調控,當Her2活化時能抑制AR-S81的磷酸化,隨著HRG處理時間越長AR-S81磷酸化程度越低,這個磷酸化的位點關係到AR的穩定性,AR-S81磷酸化的降低間接也導致AR趨於不穩定並觀察到總體蛋白量下降。而利用siRNA knockdown Her2的基因表現,也發現AR的表現量隨著給予siRNA的濃度越高而增加。若給予目前的臨床用藥Lapatinib (Her2 inhibitor),在細胞生長受抑制下,則可以發現AR-S81增加且p27蛋白表現量也隨著增加。AR在細胞中的位置也是一個值得探討的議題。從核質分離及免疫染色中的結果顯示,Lapatinib阻斷Her2之後,使得細胞質中的AR蛋白量降低,細胞核中的pS81-AR提高且p27表現量增加。以上結果顯示AR在乳癌細胞中扮演抑制乳癌細胞增生的重要角色且AR的上游可受到Her2的調控。透過了解AR在乳癌中的定位,希望對於未來乳癌的治療方向能所助益。

According to the statistics data, breast cancer is a leading cancer in Taiwan. There are about 2,000 people die of breast cancer every year, and the number of deaths has increased steadily. It is important to find out how does breast cancer begin, develop and metastasis. There are several methods for breast cancer treatment: like surgery, chemotherapy, radiotherapy, hormone therapy and target therapy. Because of the development in molecular biology, we can find the subtle changes by gene chip and analyze which gene is much more active in breast cancer, this gene will be the major target in the treatment of breast cancer, so called target therapy. In the recent studies, Estrogen receptor (ER), Progesterone receptor (PR) and Human epidermal growth factor receptor-2 (Her2) has become the major targets in the treatment of breast cancer. Triple-negative breast cancer (TNBC) accounts for approximately 12%~20% of breast cancers. This subtype of breast cancer lacks expression ER, PR and Her2. TNBC is a poor prognostic factor for disease-free and overall survival; no effective specific targeted therapy is readily available for TNBC. Therefore, to find new molecular target becomes an important research topic, androgen receptor (AR) is one of them. Here we want to discuss the role of AR in breast cancer. The MTT assay and cell counting assay show that AR activation decreased the cell proliferation of MDA-MB-453 cells. it might through the increase of p27 protein level to down-regulation cell cycle. On the other hand, Her2 activation could down-regulate the AR Serine81 phosphorylation and decrease AR protein level. In our previous study, Serine81 (Ser81) is the highest stoichiomertric phosphorylation site on AR and involes in stabilization of AR. Knockdown Her2 expression by siRNA could increase the AR protein level. Use the Her2 inhibitor, Lapatinib also found increases of both AR Ser81 phosphorylation and p27 protein level . All the data show that Her2 is important to androgen receptor expression and phosphorylation in estrogen receptor negative breast cancer cells MDA-MB-453. Finally, we hope to understand the understanding of AR in breast cancer, can contribute to the diagnosis and treatment of breast cancer.
URI: http://hdl.handle.net/11455/20332
其他識別: U0005-2308201212370600
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