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トリプルネガティブ乳癌におけるグルココルチコイド作用の臨床病理学的意義;アンドロゲンシグナルとの相互作用

金井 綾子 東北大学

2020.03.25

概要

トリプルネガティブ乳癌 (TNBC; Triple-negative breast cancer) は最も予後不良なサブタイプの乳癌であるが、現時点で推奨される全身療法は化学療法のみであり、治療標的となりうるバイオマーカーの同定が求められている。近年、TNBC におけるグルココルチコイド受容体 (GR; Glucocorticoid receptor) やアンドロゲン受容体 (AR; Androgen receptor) の重要性が着目されているが、いずれも未解明の点が多い。そこで本研究では、TNBC における GR の発現意義やグルココルチコイド (GC; Glucocorticoid) が細胞動態に与える影響、及び GR と AR の相互作用を解明することを目的とした。

まず TNBC 組織を用いて、GR, AR ならびに GC 代謝酵素である 11β ヒドロキシ脱水素酵素タイプ 1 (11βHSD1; 11β-hydroxysteroid dehydrogenase type 1) 及び 11β ヒドロキシ脱水素酵素タイプ 2 (11βHSD2; 11β-hydroxysteroid dehydrogenase type 2) の発現動態と臨床病理学的因子との関係を免疫組織化学的に検討した。その結果、TNBC 症例において GR 陽性症例では陰性症例と比して臨床予後が有意に低下し、また AR 陽性症例では陰性症例と比して組織学的グレード及びKi-67 labeling index (LI) の平均値が有意に低かった。さらに GR 陽性 TNBC 症例では、AR の発現は再発リスクを有意に低下させた。

続いて上記の臨床検体で得られた結果の背景をさらに探求するため、乳癌細胞株を用いて、デキサメサゾン(DEX; Dexamethasone)及びジヒドロテストステロン(DHT; Dihydrotestosterone)が細胞増殖能や遊走能、GC 応答遺伝子の mRNA 発現に与える影響を検討した。その結果、GR/AR 共陽性 TNBC 細胞株である AR 導入 HCC38 において、DEX により有意に促進した細胞遊走能は DHT により抑制された。また DEX により有意に増加した Serum and glucocorticoid-regulated kinase-1(SGK1)の mRNA 発現も DHT により抑制された。

以上より、TNBC において GC が細胞遊走能を促進させることで、GR の発現が予後の低下と関係することを初めて示すことができた。さらにこの GC による予後の低下は、アンドロゲンを投与することで改善する可能性も示唆され、今後の臨床的な検討が期待される。

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参考文献

1. 厚生労働省「全国がん罹患数 2016 年速報」

2. 国立がん研究センターがん情報サービス「がん登録・統計」

3. 日本乳癌学会: 乳癌診療ガイドライン 2 疫学・診断編 2018 年版. 金原出版株式会社. 2018 年

4. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747-52.

5. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869-74.

6. Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011;22:1736-47.

7. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24:2206-23.

8. Coates AS, Winer EP, Goldhirsch A, et al. Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 2015;26:1533-46.

9. Curigliano G, Burstein HJ, E PW, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. 2019;30:1181.

10. Skor MN, Wonder EL, Kocherginsky M, et al. Glucocorticoid receptor antagonism as a novel therapy for triple-negative breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013;19:6163-72.

11. Bosch A, Eroles P, Zaragoza R, et al. Triple-negative breast cancer: molecular features, pathogenesis, treatment and current lines of research. Cancer treatment reviews. 2010;36:206-15.

12. de Ruijter TC, Veeck J, de Hoon JP, et al. Characteristics of triple-negative breast cancer. Journal of cancer research and clinical oncology. 2011;137:183-92.

13. McNamara KM, Yoda T, Miki Y, et al. Androgenic pathway in triple negative invasive ductal tumors: its correlation with tumor cell proliferation. Cancer Sci. 2013;104:639-46.

14. McNamara KM, Yoda T, Takagi K, et al. Androgen receptor in triple negative breast cancer. The Journal of steroid biochemistry and molecular biology. 2013;133:66-76.

15. Wang C, Pan B, Zhu H, et al. Prognostic value of androgen receptor in triple negative breast cancer: A meta-analysis. Oncotarget. 2016;7:46482-91.

16. Ricciardelli C, Bianco-Miotto T, Jindal S, et al. The Magnitude of Androgen Receptor Positivity in Breast Cancer is Critical for Reliable Prediction of Disease Outcome. Clinical cancer research : an official journal of the American Association for Cancer Research. 2018.

17. Sunar V, H TD, Sarici F, et al. Association between androgen receptor status and prognosis in triple negative breast cancer. Journal of BUON : official journal of the Balkan Union of Oncology. 2018;23:1325-30.

18. Choi JE, Kang SH, Lee SJ, et al. Androgen receptor expression predicts decreased survival in early stage triple-negative breast cancer. Annals of surgical oncology. 2015;22:82-9.

19. Belova L, Delgado B, Kocherginsky M, et al. Glucocorticoid receptor expression in breast cancer associates with older patient age. Breast cancer research and treatment. 2009;116:441-7.

20. Abduljabbar R, Negm OH, Lai CF, et al. Clinical and biological significance of glucocorticoid receptor (GR) expression in breast cancer. Breast cancer research and treatment. 2015;150:335-46.

21. Baker GM, Murphy T, Block T, et al. Development and validation of an immunohistochemistry assay to assess glucocorticoid receptor expression for clinical trials of mifepristone in breast cancer. Cancer Manag Res. 2015;7:361-8.

22. Chen Z, Lan X, Wu D, et al. Ligand-dependent genomic function of glucocorticoid receptor in triple-negative breast cancer. Nat Commun. 2015;6:8323.

23. West DC, Kocherginsky M, Tonsing-Carter EY, et al. Discovery of a Glucocorticoid Receptor (GR) Activity Signature Using Selective GR Antagonism in ER-Negative Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2018;24:3433-46.

24. Burnstein KL, Maiorino CA, Dai JL, et al. Androgen and glucocorticoid regulation of androgen receptor cDNA expression. Mol Cell Endocrinol. 1995;115:177-86.

25. Xie N, Cheng H, Lin D, et al. The expression of glucocorticoid receptor is negatively regulated by active androgen receptor signaling in prostate tumors. International journal of cancer. 2015;136:E27-38.

26. Baschant U, Tuckermann J. The role of the glucocorticoid receptor in inflammation and immunity. The Journal of steroid biochemistry and molecular biology. 2010;120:69-75.

27. Krozowski Z, Li KX, Koyama K, et al. The type I and type II 11beta-hydroxysteroid dehydrogenase enzymes. The Journal of steroid biochemistry and molecular biology. 1999;69:391-401.

28. Pan D, Kocherginsky M, Conzen SD. Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer. Cancer research. 2011;71:6360-70.

29. Mikosz CA, Brickley DR, Sharkey MS, et al. Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. The Journal of biological chemistry. 2001;276:16649-54.

30. Wu W, Chaudhuri S, Brickley DR, et al. Microarray analysis reveals glucocorticoid-regulated survival genes that are associated with inhibition of apoptosis in breast epithelial cells. Cancer research. 2004;64:1757-64.

31. Wu W, Pew T, Zou M, et al. Glucocorticoid receptor-induced MAPK phosphatase-1 (MPK-1) expression inhibits paclitaxel-associated MAPK activation and contributes to breast cancer cell survival. The Journal of biological chemistry. 2005;280:4117-24.

32. Pang D, Kocherginsky M, Krausz T, et al. Dexamethasone decreases xenograft response to Paclitaxel through inhibition of tumor cell apoptosis. Cancer biology & therapy. 2006;5:933-40.

33. Li Z, Dong J, Zou T, et al. Dexamethasone induces docetaxel and cisplatin resistance partially through up-regulating Kruppel-like factor 5 in triple-negative breast cancer. Oncotarget. 2017;8:11555-65.

34. Tang Z, Ding S, Huang H, et al. HDAC1 triggers the proliferation and migration of breast cancer cells via upregulation of interleukin-8. Biological chemistry. 2017;398:1347-56.

35. Zhang Y. Ganoderma lucidum (Reishi) suppresses proliferation and migration of breast cancer cells via inhibiting Wnt/beta-catenin signaling. Biochemical and biophysical research communications. 2017;488:679-84.

36. Kong Q, Qiu M. Long noncoding RNA SNHG15 promotes human breast cancer proliferation, migration and invasion by sponging miR-211-3p. Biochemical and biophysical research communications. 2018;495:1594-600.

37. Chen S, Wang J, Yu G, et al. Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity. The Journal of biological chemistry. 1997;272:14087-92.

38. McCarty KS, Jr., Miller LS, Cox EB, et al. Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Archives of pathology & laboratory medicine. 1985;109:716-21.

39. Suzuki T, Miki Y, Moriya T, et al. 5Alpha-reductase type 1 and aromatase in breast carcinoma as regulators of in situ androgen production. International journal of cancer. 2007;120:285-91.

40. McNamara KM, Yoda T, Miki Y, et al. Androgen receptor and enzymes in lymph node metastasis and cancer reoccurrence in triple-negative breast cancer. Int J Biol Markers. 2015;30:e184-9.

41. Dowsett M, Nielsen TO, A'Hern R, et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. Journal of the National Cancer Institute. 2011;103:1656-64.

42. Tamaki K, Ishida T, Tamaki N, et al. Analysis of clinically relevant values of Ki-67 labeling index in Japanese breast cancer patients. Breast cancer (Tokyo, Japan). 2014;21:325-33.

43. Itani OA, Liu KZ, Cornish KL, et al. Glucocorticoids stimulate human sgk1 gene expression by activation of a GRE in its 5'-flanking region. American journal of physiology Endocrinology and metabolism. 2002;283:E971-9.

44. So AY, Chaivorapol C, Bolton EC, et al. Determinants of cell- and gene-specific transcriptional regulation by the glucocorticoid receptor. PLoS genetics. 2007;3:e94.

45. Buxant F, Engohan-Aloghe C, Noel JC. Estrogen receptor, progesterone receptor, and glucocorticoid receptor expression in normal breast tissue, breast in situ carcinoma, and invasive breast cancer. Appl Immunohistochem Mol Morphol. 2010;18:254-7.

46. Hall RE, Birrell SN, Tilley WD, et al. MDA-MB-453, an androgen-responsive human breast carcinoma cell line with high level androgen receptor expression. European journal of cancer (Oxford, England : 1990). 1994;30a:484-90.

47. Birrell SN, Bentel JM, Hickey TE, et al. Androgens induce divergent proliferative responses in human breast cancer cell lines. The Journal of steroid biochemistry and molecular biology. 1995;52:459-67.

48. Doane AS, Danso M, Lal P, et al. An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene. 2006;25:3994-4008.

49. Naderi A, Hughes-Davies L. A functionally significant cross-talk between androgen receptor and ErbB2 pathways in estrogen receptor negative breast cancer. Neoplasia. 2008;10:542-8.

50. Chia KM, Liu J, Francis GD, et al. A feedback loop between androgen receptor and ERK signaling in estrogen receptor-negative breast cancer. Neoplasia. 2011;13:154-66.

51. Isikbay M, Otto K, Kregel S, et al. Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Hormones & cancer. 2014;5:72-89.

52. Luecke HF, Yamamoto KR. The glucocorticoid receptor blocks P-TEFb recruitment by NFkappaB to effect promoter-specific transcriptional repression. Genes & development. 2005;19:1116-27.

53. Lempiainen JK, Niskanen EA, Vuoti KM, et al. Agonist-specific Protein Interactomes of Glucocorticoid and Androgen Receptor as Revealed by Proximity Mapping. Molecular & cellular proteomics : MCP. 2017;16:1462-74.

54. Gennari A, Salvadori B, Tognoni A, et al. Rapid intravenous premedication with dexamethasone prevents hypersensitivity reactions to paclitaxel. Ann Oncol. 1996;7:978-9.

55. Lin KT, Wang LH. New dimension of glucocorticoids in cancer treatment. Steroids. 2016;111:84-8.

56. デカドロン錠 添付文書

57. Nanda R, Stringer-Reasor EM, Saha P, et al. A randomized phase I trial of nanoparticle albumin-bound paclitaxel with or without mifepristone for advanced breast cancer. Springerplus. 2016;5:947.

58. Yamamoto Y, Kawano I, Iwase H. Nab-paclitaxel for the treatment of breast cancer: efficacy, safety, and approval. OncoTargets and therapy. 2011;4:123-36.

59. Roila F, Molassiotis A, Herrstedt J, et al. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol. 2016;27:v119-v33.

60. Kerns J, Steinauer J. Management of postabortion hemorrhage: release date November 2012 SFP Guideline #20131. Contraception. 2013;87:331-42.

61. ボナゾール錠 添付文書

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