Сигнальные пути, регулируемые эстрогенами, и их роль в опухолевой прогрессии: новые факты и направления поиска

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Более сорока лет антиэстроген тамоксифен успешно применяется в терапии рака молочной железы, но основной проблемой в его применении до настоящего времени остается развитие у больных гормональной резистентности, существенно ограничивающей эффективность антиэстрогеновой терапии. За последние годы достигнут значительный прогресс в понимании механизмов формирования гормональной резистентности и выявлены новые молекулярные пути, поддерживающие рост опухоли в условиях «выключения» рецепторов эстрогенов. В обзоре проанализированы результаты исследований, в том числе выполненных в ФГБУ «РОНЦ им. Н. Н. Блохина» РАМН, посвященных новым аспектам этой тематики – активности сигнальных путей HIF-1α / VEGF, эпителиально-мезенхимального перехода и mTOR / AMPK; показано, как на молекулярном уровне формируется устойчивость опухоли к действию гормональных цитостатических препаратов. Некоторые из сигнальных белков рассмотрены в качестве показателей прогноза и / или перспективных мишеней таргетной терапии резистентных форм рака молочной железы.

Об авторах

М. А. Красильников

ФГБУ «РОНЦ им. Н. Н. Блохина» РАМН, Москва

Автор, ответственный за переписку.
Email: krasilnikovm@main.crc.umos.ru
Россия

А. М. Щербаков

ФГБУ «РОНЦ им. Н. Н. Блохина» РАМН, Москва

Email: fake@neicon.ru
Россия

Список литературы

  1. Jensen E.V., DeSombre E.R. Estrogenreceptor interaction. Science 1973;182(4108):126–34.
  2. Герштейн Е.С., Кушлинский Н.Е. Биологические маркеры рака молочной железы: методологические аспекты и клинические рекомендации. Маммология 2005;1:65–9.
  3. Красильников М.А. Современные подходы к изучению механизма эстроген-независимого роста опухолей молочной железы. Вопросы онкологии 2004;50(4):399–405.
  4. Clarke R., Liu M.C., Bouker K.B. et al. Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. Oncogene 2003;22(47): 7316–39.
  5. Lee M., Lee C.S., Tan P.H. Hormone receptor expression in breast cancer: postanalytical issues. J Clin Pathol 2013;66(6):478–84.
  6. Normanno N., Di Maio M., De Maio E. et al. Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer. Endocr Relat Cancer 2005;12(4):721–47.
  7. Jordan V.C. Targeting antihormone resistance in breast cancer: a simple solution. Ann Oncol 2003;14(7):969–70.
  8. Jalava P., Kuopio T., Huovinen R. et al. Immunohistochemical staining of estrogen and progesterone receptors: aspects for evaluating positivity and defining the cutpoints. Anticancer Res 2005;25(3c):2535–42.
  9. Henderson B.E., Ponder B.A.J., Ross R.K. Hormones, genes, and cancer. New York: Oxford University Press, 2003.
  10. Берштейн Л.М. Современная эндокринология гормонозависимых опухолей. Вопросы онкологии 2002;48(4):496–504.
  11. Красильников М.А. Сигнальные пути, регулируемые фосфатидилинозит-3-киназой, и их значение для роста, выживаемости и злокачественной трансформации клеток. Биохимия 2000;65(1):68–78.
  12. Kurebayashi J. Endocrine-resistant breast cancer: underlying mechanisms and strategies for overcoming resistance. Breast Cancer 2003;10(2):112–9.
  13. Roop R.P., Ma C.X. Endocrine resistance in breast cancer: molecular pathways and rational development of targeted therapies. Future Oncol 2012;8(3):273–92.
  14. Garcia-Becerra R., Santos N., Diaz L. et al. Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance. Int J Mol Sci 2012;14(1):108–45.
  15. Laenkholm A.V., Knoop A., Ejlertsen B. et al. ESR1 gene status correlates with estrogen receptor protein levels measured by ligand binding assay and immunohistochemistry. Mol ncol 2012;6(4):428–36.
  16. Conway K., Parrish E., Edmiston S.N. et al. Risk factors for breast cancer characterized by the estrogen receptor alpha A908G (K303R) mutation. Breast cancer research: BCR 2007;9(3):R36.
  17. Generali D., Berruti A., Brizzi M.P. et al. Hypoxia-inducible factor-1alpha expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer. Clin Cancer Res 2006;12(15):4562–8.
  18. Generali D., Buffa F.M., Berruti A. et al. Phosphorylated ERalpha, HIF-1alpha, and MAPK signaling as predictors of primary endocrine treatment response and resistance in patients with breast cancer. J Clin Oncol 2009;27(2):227–34.
  19. Span P.N., Bussink J., Manders P. et al. Carbonic anhydrase-9 expression levels and prognosis in human breast cancer: association with treatment outcome. Br J Cancer 2003;89(2):271–6.
  20. Mabjeesh N.J., Amir S. Hypoxiainducible factor (HIF) in human tumorigenesis. Histol Histopathol 2007;22(5):559–72.
  21. Ke Q., Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 2006;70(5):1469–80.
  22. Kimbro K.S., Simons J.W. Hypoxiainducible factor-1 in human breast and prostate cancer. Endocr Relat Cancer 2006;13(3):739–49.
  23. Liao D., Johnson R.S. Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev 2007;26(2):281–90.
  24. Scherbakov A.M., Stefanova L.B., Sorokin D.V. et al. Snail/beta-catenin signaling protects breast cancer cells from hypoxia attack. Exp Cell Res 2013;319(20):3150–9.
  25. Stoner M., Saville B., Wormke M. et al. Hypoxia induces proteasome-dependent degradation of estrogen receptor alpha in ZR-75 breast cancer cells. Mol Endocrinol 2002;16(10):2231–42.
  26. Yi J.M., Kwon H.Y., Cho J.Y. et al. Estrogen and hypoxia regulate estrogen receptor alpha in a synergistic manner. Biochem Biophys Res Commun 2009;378(4):842–6.
  27. Kurebayashi J., Otsuki T., Moriya T. et al. Hypoxia reduces hormone responsiveness of human breast cancer cells. Jpn J Cancer Res 2001;92(10):1093–101.
  28. Cho J., Kim D., Lee S. et al. Cobalt chloride-induced estrogen receptor alpha down-regulation involves hypoxia-inducible factor-1alpha in MCF-7 human breast cancer cells. Mol Endocrinol 2005;19(5):1191–9.
  29. Kronblad A., Hedenfalk I., Nilsson E. et al. ERK1/2 inhibition increases antiestrogen treatment efficacy by interfering with hypoxia-induced downregulation of ERalpha: a combination therapy potentially targeting hypoxic and dormant tumor cells. Oncogene 2005;24(45):6835–41.
  30. Park Y.M., Cho J.Y., Koo Y.D. et al. Effects of inhibiting the proteasomal degradation of estrogen receptor alpha on estrogen receptor alpha activation under hypoxic conditions. Biol Pharm Bull 2009;32(12):2057–60.
  31. Cho J., Bahn J.J., Park M. et al. Hypoxic activation of unoccupied estrogen- eceptoralpha is mediated by hypoxia-inducible factor-1 alpha. J Steroid Biochem Mol Biol 2006;100(1-3):18–23.
  32. Cooper C., Liu G.Y., Niu Y.L. et al. Intermittent hypoxia induces proteasomedependent down-regulation of estrogen receptor alpha in human breast carcinoma. Clin Cancer Res 2004;10(24):8720–7.
  33. Стефанова Л.Б., Щербаков А.М., Андреева О.Е. и др. Чувствительность к гипоксии культивируемых in vitro клеток рака молочной железы: роль аппарата рецептора эстрогенов. Вопросы биологической, медицинской и фармацевтической химии 2012;10:60–3.
  34. Franovic A., Gunaratnam L., Smith K. et al. Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. Proceedings of the National Academy of Sciences of the United States of America 2007;104(32):13092–7.
  35. Swinson D.E., O'Byrne K.J. Interactions between hypoxia and epidermal growth factor receptor in non-small-cell lung cancer. Clin Lung Cancer 2006;7(4):250–6.
  36. Nishi H., Nishi K.H., Johnson A.C. Early Growth Response-1 gene mediates upregulation of epidermal growth factor receptor expression during hypoxia. Cancer Res 2002;62(3):827–34.
  37. Yamamoto Y., Ibusuki M., Okumura Y. et al. Hypoxia-inducible factor 1alpha is closely linked to an aggressive phenotype in breast cancer. Breast cancer research and treatment 2008;110(3):465–75.
  38. Higgins M.J., Baselga J. Targeted therapies for breast cancer. J Clin Invest 2011;121(10):3797–803.
  39. Osborne C.K., Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 2011;62:233–47.
  40. Stopeck A.T., Brown-Glaberman U., Wong H.Y. et al. The role of targeted therapy and biomarkers in breast cancer treatment. Clin Exp Metastasis 2012;29(7):807–19.
  41. Malaguti P., Vari S., Cognetti F. et al. The Mammalian target of rapamycin inhibitors in breast cancer: current evidence and future directions. Anticancer Res 2013;33(1):21–8.
  42. Normanno N., Morabito A., De Luca A. et al. Target-based therapies in breast cancer: current status and future perspectives. Endocrine-related cancer 2009;16(3):675–702.
  43. Mohd Sharial M.S., Crown J., Hennessy B.T. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer. Ann Oncology 2012;23(12):3007–16.
  44. Lundgren K., Holm C., Landberg G. Hypoxia and breast cancer: prognostic and therapeutic implications. Cellular and molecular life sciences: CMLS 2007;64(24):3233–47.
  45. Pouyssegur J., Dayan F., Mazure N.M. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006;441(7092):437–43.
  46. Semenza G.L. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3(10):721–32.
  47. Kajdaniuk D., Marek B., Foltyn W. et al. Vascular endothelial growth factor (VEGF) – part 2: in endocrinology and oncology. Endokrynol Pol 2011;62(5):456–64.
  48. Bareschino M.A., Schettino C., Colantuoni G. et al. The role of antiangiogenetic agents in he treatment of breast cancer. Curr Med Chem 2011;18(33):5022–32.
  49. Щербаков А.М., Герштейн Е.С., Ошкина Е.В. и др. Фосфорилированная киназа AKT1, фактор роста эндотелия сосудов и его рецепторы: внутриопухолевое содержание и прогностическое значение у больных раком молочной железы. Молекулярная медицина 2014;4:20–4.
  50. Molitoris K.H., Kazi A.A., Koos R.D. Inhibition of oxygen-induced hypoxiainducible factor-1alpha degradation unmasks estradiol induction of vascular endothelial growth factor expression in ECC-1 cancer cells in vitro. Endocrinology 2009;150(12):5405–14.
  51. Ruohola J.K., Valve E.M., Karkkainen M.J. et al. Vascular endothelial growth factors are differentially regulated by steroid hormones and antiestrogens in breast cancer cells. Mol Cell Endocrinol 1999;149(1-2):29–40.
  52. Bogin L., Degani H. Hormonal regulation of VEGF in orthotopic MCF7 human breast cancer. Cancer Res 2002;62(7):1948–51.
  53. Scherbakov A.M., Lobanova Y.S., Shatskaya V.A. et al. Activation of mitogenic pathways and sensitization to estrogeninduced apoptosis: two independent characteristics of tamoxifen-resistant breast cancer cells? Breast Cancer Res Treat 2006;100(1):1–11.
  54. Patel R.R., Sengupta S., Kim H.R. et al. Experimental treatment of oestrogen receptor (ER) positive breast cancer with tamoxifen and brivanib alaninate, a VEGFR-2/FGFR-1 kinase inhibitor: a potential clinical application of angiogenesis inhibitors. European journal of cancer 2010;46(9):1537–53.
  55. Kumar B.N., Rajput S., Dey K.K. et al. Celecoxib alleviates tamoxifen-instigated angiogenic effects by ROS-dependent VEGF/VEGFR2 autocrine signaling. BMC Cancer 2013;13:273.
  56. Qu Z., Van Ginkel S., Roy A.M. et al. Vascular endothelial growth factor reduces tamoxifen efficacy and promotes metastatic colonization and desmoplasia in breast tumors. Cancer Res 2008;68(15):6232–40.
  57. Acloque H., Adams M.S., Fishwick K. et al. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest 2009;119(6):1438–49.
  58. Zeisberg M., Neilson E.G. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 2009;119(6):1429–37.
  59. Nieto M.A. Epithelial-Mesenchymal Transitions in development and disease: old views and new perspectives. Int J Dev Biol 2009;53(8–10):1541–7.
  60. De Wever O., Pauwels P., De Craene B. et al. Molecular and pathological signatures of epithelial-mesenchymal transitions at the cancer invasion front. Histochem Cell Biol 2008;130(3):481–94.
  61. Alves C.C., Carneiro F., Hoefler H. et al. Role of the epithelial-mesenchymal transition egulator Slug in primary human cancers. Front Biosci 2009;14:3035–50.
  62. Becker K.F., Rosivatz E., Blechschmidt K. et al. Analysis of the E-cadherin repressor Snail in primary human cancers. Cells Tissues Organs 2007;185(1–3):204–12.
  63. Come C., Arnoux V., Bibeau F. et al. Roles of the transcription factors snail and slug during mammary morphogenesis and breast carcinoma progression. J Mammary Gland Biol Neoplasia 2004;9(2):183–93.
  64. Hugo H.J., Kokkinos M.I., Blick T. et al. Defining the E-cadherin repressor interactome in epithelial-mesenchymal transition: the PMC42 model as a case study. Cells Tissues Organs 2011;193(1-2):23–40.
  65. Blechschmidt K., Kremmer E., Hollweck R. et al. The E-cadherin repressor snail plays a role in tumor progression of endometrioid adenocarcinomas. Diagn Mol Pathol 2007;16(4):222–8.
  66. Park S.H., Cheung L.W., Wong A.S. et al. Estrogen regulates Snail and Slug in the down-regulation of E-cadherin and induces metastatic potential of ovarian cancer cells through estrogen receptor alpha. Mol Endocrinol 2008;22(9):2085–98.
  67. Ye Y., Xiao Y., Wang W. et al. ERalpha suppresses slug expression directly by transcriptional repression. Biochem J 2008;416(2):179–87.
  68. Dhasarathy A., Kajita M., Wade P.A. The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-alpha. Mol Endocrinol 2007;21(12):2907–18.
  69. Fujita N., Jaye D.L., Kajita M. et al. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell 2003;113(2):207–19.
  70. Scherbakov A.M., Andreeva O.E., Shatskaya V.A. et al. The relationships between snail1 and estrogen receptor signaling in breast cancer cells. J Cell Biochem 2012;113(6):2147–55.
  71. Andreeva O.E., Shcherbakov A.M., Shatskaia V.A. et al. The role of transcription factor Snail1 in the regulation of hormonal sensitivity of in vitro cultured breast cancer cells. Voprosy onkologii 2012;58(1):71–6.
  72. Geradts J., de Herreros A.G., Su Z. et al. Nuclear Snail1 and nuclear ZEB1 protein expression in invasive and intraductal human breast carcinomas. Hum Pathol 2011;42(8):1125–31.
  73. Zhou G., Dada L.A., Wu M. et al. Hypoxia-induced alveolar epithelialmesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1. Am J Physiol Lung Cell Mol Physiol 2009;297(6):L1120–1130.
  74. Kim W.Y., Perera S., Zhou B. et al. HIF2alpha cooperates with RAS to promote lung tumorigenesis in mice. J Clin Invest 2009;119(8):2160–70.
  75. Moen I., Oyan A.M., Kalland K.H. et al. Hyperoxic treatment induces mesenchymalto- epithelial transition in a rat adenocarcinoma model. PloS One 2009;4(7):e6381.
  76. Hill R.P., Marie-Egyptienne D.T., Hedley D.W. Cancer stem cells, hypoxia and metastasis. Semin Radiat Oncol 2009;19(2):106–11.
  77. Lundgren K., Nordenskjold B., Landberg G. Hypoxia, Snail and incomplete epithelial-mesenchymal transition in breast cancer. Br J Cancer 2009;101(10):1769–81.
  78. Щербаков А.М., Стефанова Л.Б., Андреева О.Е. и др. Роль Snail-сигнального пути в развитии устойчивости к гипоксии клеток рака молочной железы. Технологии живых систем 2012;9(9):63–7.
  79. Mak P., Leav I., Pursell B. et al. ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading. Cancer Cell 2010;17(4):319–32.
  80. Hartman J., Lindberg K., Morani A. et al. Estrogen receptor beta inhibits angiogenesis and growth of T47D breast cancer xenografts. Cancer Res 2006;66(23):11207–13.
  81. Mosselman S., Polman J., Dijkema R. ER beta: identification and characterization of a novel human estrogen receptor. FEBS letters 1996;392(1):49–53.
  82. Leitman D.C., Paruthiyil S., Vivar O.I. et al. Regulation of specific target genes and biological responses by estrogen receptor subtype agonists. Curr Opin Pharmacol 2010;10(6):629–36.
  83. Fox E.M., Davis R.J., Shupnik M.A. ERbeta in breast cancer--onlooker, passive player, or active protector? Steroids 2008;73(11):1039–51.
  84. Murphy L.C., Watson P.H. Is oestrogen receptor-beta a predictor of endocrine therapy responsiveness in human breast cancer? Endocrine-related cancer 2006;13(2):327–34.
  85. Li W., Winters A., Poteet E. et al. Involvement of estrogen receptor beta5 in the progression of glioma. Brain Res 2013;1503:97–107.
  86. Al-Bader M.D., Malatiali S.A., Redzic Z.B. Expression of estrogen receptor alpha and beta in rat astrocytes in primary culture: effects of hypoxia and glucose deprivation. Physiol Res 2011;60(6):951–60.
  87. Lim W., Park Y., Cho J. et al. Estrogen receptor beta inhibits transcriptional activity of hypoxia inducible factor-1 through the downregulation of arylhydrocarbon receptor nuclear translocator. Breast Cancer Res: BCR 2011;13(2):R32.
  88. Lim W., Cho J., Kwon H.Y. et al. Hypoxia-inducible factor 1 alpha activates and is inhibited by unoccupied estrogen receptor beta. FEBS letters 2009;583(8):1314–8.
  89. Mak P., Chang C., Pursell B. et al. Estrogen receptor beta sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription. Proceedings of the National Academy of Sciences of the United States of America 2013;110(12):4708–13.
  90. Hartman J., Strom A., Gustafsson J.A. Estrogen receptor beta in breast cancer – diagnostic and therapeutic implications. Steroids 2009;74(8):635–41.
  91. Zhao C., Lam E.W., Sunters A. et al. Expression of estrogen receptor beta isoforms in normal breast epithelial cells and breast cancer: regulation by methylation. Oncogene 2003;22(48):7600–6.
  92. Pettersson K., Delaunay F., Gustafsson J.A. Estrogen receptor beta acts as a dominant regulator of estrogen signaling. Oncogene 2000;19(43):4970–8.
  93. Murphy L.C., Leygue E., Niu Y. et al. Relationship of coregulator and oestrogen receptor isoform expression to de novo tamoxifen resistance in human breast cancer. Br J Cancer 2002;87(12):1411–6.
  94. Iwase H., Zhang Z., Omoto Y. et al. Clinical significance of the expression of estrogen receptors alpha and beta for endocrine therapy of breast cancer. Cancer Chemother Pharmacol 2003;52 Suppl 1:S34–38.
  95. Rody A., Holtrich U., Solbach C. et al. Methylation of estrogen receptor beta promoter correlates with loss of ER-beta expression in mammary carcinoma and is an early indication marker in premalignant lesions. Endocrine-related cancer 2005;12(4):903–16.
  96. Stone A., Valdes-Mora F., Gee J.M. et al. amoxifen-induced epigenetic silencing of oestrogen-regulated genes in anti-hormone resistant breast cancer. PLoS One 2012;7(7):e40466.
  97. Alayev A., Holz M.K. mTOR signaling for biological control and cancer. J Cell Physiol 2013;228(8):1658–64.
  98. Красильников М.А., Жуков Н.В. Сигнальный путь mTOR: новая мишень терапии опухолей. Современная онкология 2010;12(2):9–16.
  99. Walsh S., Flanagan L., Quinn C. et al. mTOR in breast cancer: differential expression in triple-negative and non-triplenegative tumors. Breast 2012;21(2):178–82.
  100. Семиглазова Т.Ю., Семиглазов В.В., Филатова Л.В. и др. Новый подход преодолению резистентности к гормонотерапии рака молочной железы. Фарматека 2012;18:50–6.
  101. Vilquin P., Villedieu M., Grisard E. et al. Molecular characterization of anastrozole resistance in breast cancer: pivotal role of the Akt/mTOR pathway in the emergence of de novo or acquired resistance and importance of combining the allosteric Akt inhibitor MK- 2206 with an aromatase inhibitor. Int J Cancer (Journal international du cancer) 2013;133(7):1589–602.
  102. Arsham A.M., Howell J.J., Simon M.C. A novel hypoxia-inducible factorindependent hypoxic response regulating mammalian target of rapamycin and its targets. J Biol Chem 2003;278(32):29655–60.
  103. Koo J.S., Jung W. Alteration of REDD1-mediated mammalian target of rapamycin pathway and hypoxia-inducible factor-1alpha regulation in human breast cancer. Pathobiology 2010;77(6):289–300.
  104. DeYoung M.P., Horak P., Sofer A. et al. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 2008;22(2):239–51.
  105. Connolly E., Braunstein S., Formenti S. et al. Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells. Mol Cell Biol 2006;26(10):3955–65.
  106. Miller T.W., Rexer B.N., Garrett J.T. et al. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res: BCR 2011;13(6):224.
  107. Liu L., Cash T.P., Jones R.G. et al. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell 2006;21(4):521–31.
  108. Inoki K., Zhu T., Guan K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115(5):577–90.
  109. Ollila S., Makela T.P. The tumor suppressor kinase LKB1: lessons from mouse models. J Mol Cell Biol 2011;3(6):330–40.
  110. Shackelford D.B., Shaw R.J. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 2009;9(8):563–75.
  111. Sato T., Nakashima A., Guo L. et al. Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer. Oncogene 2010;29(18):2746–52.
  112. Fenton H., Carlile B., Montgomery E.A. et al. LKB1 protein expression in human breast cancer. Appl Immunohistochem Mol Morphol 2006;14(2):146–53.
  113. Korsse S.E., Peppelenbosch M.P., van Veelen W. Targeting LKB1 signaling in cancer. Biochimica et biophysica acta 2013;1835(2):194–210.

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