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Estrogen Receptor Signaling in Lung Cancer

  • P. A. Hershberger
  • J. M. Siegfried
Chapter

Abstract

More than 213,000 new cases of lung cancer were diagnosed in the United States in 2007 and more than 160,000 individuals died from their disease (Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57(1):43–66). This underscores the need for new, effective approaches to lung cancer prevention and treatment. Undoubtedly, such approaches will be developed through the discovery and further characterization of pathways on which tumor cells depend for their growth. Sex differences in lung cancer presentation point to a potential role for estrogens in the initiation and/or progression of lung cancer. In this chapter, we review the biology of the estrogen receptor (ER), preclinical studies that demonstrate that estrogen signals through ERβ to promote lung cancer growth, and the clinical trials that have emerged to assess the safety and utility of antiestrogen-based therapies in lung cancer treatment.

Keywords

Lung Cancer Epidermal Growth Factor Receptor Hormone Replacement Therapy Aromatase Inhibitor NSCLC Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Muscat JE, Wynder EL. Lung cancer pathology in smokers, ex-smokers and never smokers. Cancer Lett 1995;88(1):1–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Ryberg D, Hewer A, Phillips DH, Haugen A. Different susceptibility to smoking-induced DNA damage among male and female lung cancer patients. Cancer Res 1994;54(22):5801–3.PubMedGoogle Scholar
  3. 3.
    Mollerup S, Ryberg D, Hewer A, Phillips DH, Haugen A. Sex differences in lung CYP1A1 expression and DNA adduct levels among lung cancer patients. Cancer Res 1999;59(14): 3317–20.PubMedGoogle Scholar
  4. 4.
    Wei Q, Cheng L, Amos CI, et al. Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study. J Natl Cancer Inst 2000;92(21):1764–72.PubMedCrossRefGoogle Scholar
  5. 5.
    Patel JD, Bach PB, Kris MG. Lung cancer in US women: a contemporary epidemic. JAMA 2004;291(14):1763–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55(2):74–108.PubMedCrossRefGoogle Scholar
  7. 7.
    Frasor J, Danes JM, Komm B, Chang KCN, Lyttle CR, Katzenellenbogen BS. Profiling of Estrogen-Up- and Down-Regulated Gene Expression in Human Breast Cancer Cells: Insights into Gene Networks and Pathways Underlying Estrogenic Control of Proliferation and Cell Phenotype. Endocrinology 2003;144:4562–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 1996;93(12):5925–30.PubMedCrossRefGoogle Scholar
  9. 9.
    Mosselman S, Polman J, Dijkema R. ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett 1996;392(1):49–53.PubMedCrossRefGoogle Scholar
  10. 10.
    Delaunay F, Pettersson K, Tujague M, Gustafsson JA. Functional differences between the amino-terminal domains of estrogen receptors alpha and beta. Mol Pharmacol 2000;58(3):584–90.PubMedGoogle Scholar
  11. 11.
    Brzozowski AM, Pike AC, Dauter Z, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997;389(6652):753–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Shiau AK, Barstad D, Loria PM, et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998;95(7):927–37.PubMedCrossRefGoogle Scholar
  13. 13.
    Kushner PJ, Agard, D.A., Greene, G.L., Scanlan, T.S., Shiau, A.K., Uht, R.M., Webb, P. Estrogen receptor pathways to AP-1. Journal Steroid Biochemistry Molecular Biology 2000;74:311–7.CrossRefGoogle Scholar
  14. 14.
    Safe S, Kim K. Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways. J Mol Endocrinol 2008;41(5):263–75.PubMedCrossRefGoogle Scholar
  15. 15.
    Kininis M, Chen BS, Diehl AG, et al. Genomic analyses of transcription factor binding, histone acetylation, and gene expression reveal mechanistically distinct classes of estrogen-regulated promoters. Mol Cell Biol 2007;27(14):5090–104.PubMedCrossRefGoogle Scholar
  16. 16.
    Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90(18):1371–88.PubMedCrossRefGoogle Scholar
  17. 17.
    Shang Y, Brown, M. Molecular Determinants for the Tissue Specificity of SERMs. Science 2002;295:2465–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Osborne CK, Wakeling A, Nicholson RI. Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br J Cancer 2004;90 Suppl 1:S2-6.PubMedCrossRefGoogle Scholar
  19. 19.
    Dauvois S, Danielian PS, White R, Parker MG. Antiestrogen ICI 164,384 reduces cellular estrogen receptor content by increasing its turnover. Proc Natl Acad Sci USA 1992;89(9): 4037–41.PubMedCrossRefGoogle Scholar
  20. 20.
    Dauvois S, White R, Parker MG. The antiestrogen ICI 182780 disrupts estrogen receptor nucleocytoplasmic shuttling. J Cell Sci 1993;106 ( Pt 4):1377–88.PubMedGoogle Scholar
  21. 21.
    DeFriend DJ, Anderson E, Bell J, et al. Effects of 4-hydroxytamoxifen and a novel pure ­antioestrogen (ICI 182780) on the clonogenic growth of human breast cancer cells in vitro. Br J Cancer 1994;70(2):204–11.PubMedCrossRefGoogle Scholar
  22. 22.
    Osborne CK, Coronado-Heinsohn EB, Hilsenbeck SG, et al. Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst 1995;87(10):746–50.PubMedCrossRefGoogle Scholar
  23. 23.
    Van Den Bemd GJ, Kuiper GG, Pols HA, Van Leeuwen JP. Distinct effects on the conformation of estrogen receptor alpha and beta by both the antiestrogens ICI 164,384 and ICI 182,780 leading to opposite effects on receptor stability. Biochem Biophys Res Commun 1999;261(1):1–5.CrossRefGoogle Scholar
  24. 24.
    Peekhaus NT, Chang T, Hayes EC, et al. Distinct effects of the antiestrogen Faslodex on the stability of estrogen receptors-alpha and -beta in the breast cancer cell line MCF-7. J Mol Endocrinol 2004;32(3):987–95.PubMedCrossRefGoogle Scholar
  25. 25.
    Damdimopoulos AE, Spyrou G, Gustafsson JA. Ligands differentially modify the nuclear mobility of estrogen receptors alpha and beta. Endocrinology 2008;149(1):339–45.PubMedCrossRefGoogle Scholar
  26. 26.
    Stabile LP, Gaither Davis AL, Gubish CT, Hopkins TM, Luketich JD, Christie N, Finkelstein S, and Siegfried JM. Human Non-Small Cell Lung Tumors and Cells Derived from Normal Lung Express Both Estrogen Receptor α and β and Show Biological Responses to Estrogen. Cancer Research 2002;62:2141–50.PubMedGoogle Scholar
  27. 27.
    Hershberger PA, Stabile LP, Kanterewicz B, et al. Estrogen receptor beta (ERbeta) subtype-specific ligands increase transcription, p44/p42 mitogen activated protein kinase (MAPK) activation and growth in human non-small cell lung cancer cells. J Steroid Biochem Mol Biol 2009.Google Scholar
  28. 28.
    Lau KM, LaSpina M, Long J, Ho SM. Expression of estrogen receptor (ER)-alpha and ER-beta in normal and malignant prostatic epithelial cells: regulation by methylation and involvement in growth regulation. Cancer Res 2000;60(12):3175–82.PubMedGoogle Scholar
  29. 29.
    Belcher SM, Ma X, Le HH. Blockade of estrogen receptor signaling inhibits growth and migration of medulloblastoma. Endocrinology 2009;150(3):1112–21.PubMedCrossRefGoogle Scholar
  30. 30.
    Ciana P, DiLuccio G, Belcredito S, Pollio G, Vegeto E, Tatangelo L, Tiveron C, Maggi A. Engineering of a Mouse for the in Vivo Profiling of Estrogen Receptor Activity. Molecular Endocrinology 2001;15:1104–13.Google Scholar
  31. 31.
    Lemmen JG, Arends RJ, van Boxtel AL, van der Saag PT, van der Burg B. Tissue- and time-dependent estrogen receptor activation in estrogen reporter mice. J Mol Endocrinol 2004;32(3):689–701.PubMedCrossRefGoogle Scholar
  32. 32.
    Patrone C, Cassel TN, Pettersson K, Piao Y-S, Cheng G, Ciana P, Maggi A, Warner M, Gustafsson J-A, Nord M. Regulation of Postnatal Lung Development and Homeostasis by Estrogen Receptor β. Molecular and Cellular Biology 2003;23:8542–52.PubMedCrossRefGoogle Scholar
  33. 33.
    Morani A, Barros RP, Imamov O, et al. Lung dysfunction causes systemic hypoxia in estrogen receptor beta knockout (ERbeta−/−) mice. Proc Natl Acad Sci USA 2006;103(18):7165–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Oton AB BC, Cai C, Owonikoko T, Gooding W, Siegfried J, Ramalingam R. Comparison of survival for non-small cell lung cancer between premenopausal and postmenopausal women: An analysis of the National Surveillance, Epidemiology and End Results (SEER) Database. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings 2006;24(18 S):7038.Google Scholar
  35. 35.
    Albain KS UJ, Gotay CC, Davies AM, Edelman M, Herbst RS, Kelly K, Williamson S, Wozniak AJ, Gandara DR. Toxicity and survival by sex in patients with advanced non-small cell lung carcinoma on modern Southwest Oncology Group (SWOG) trials. Journal of Clinical Oncology ASCO Annual Meeting Proceedings 2007;25(18 S):7549.Google Scholar
  36. 36.
    Ross H OF, Bandstra B, Sandalic L, Bianco J, Bonomi P, Singer JW. Serum-free estradiol (E2) levels are prognostic in men with chemotherapy-naive advanced non-small cell lung cancer and performance status (PS) 2. Journal of Clinical Oncology ASCO Annual Meeting Proceedings 2007;25(18 S):7683.Google Scholar
  37. 37.
    La Vecchia C. Hormone replacement therapy in menopause and lung cancer: an update. Eur J Cancer Prev 2006;15(3):189–90.PubMedCrossRefGoogle Scholar
  38. 38.
    Ganti AK, Sahmoun AE, Panwalkar AW, Tendulkar KK, Potti A. Hormone replacement therapy is associated with decreased survival in women with lung cancer. J Clin Oncol 2006;24(1):59–63.PubMedCrossRefGoogle Scholar
  39. 39.
    Ayeni O, Robinson A. Hormone replacement therapy and outcomes for women with non-small-cell lung cancer: can an association be confirmed? Curr Oncol 2009;16(3):21–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Chlebowski R.T. SA, Wakelee H., Anderson G.L., Stefanick M.L., Manson J.E., Chien J.W., Chen C., Wactawski-Wende J., Gass M. Non-small cell lung cancer and estrogen plus progestin use in postmenopausal women in the Women’s Health Initiative randomized clinical trial. J Clin Oncol 2009;27:18 s.CrossRefGoogle Scholar
  41. 41.
    Hammoud Z, Tan B, Badve S, Bigsby RM. Estrogen promotes tumor progression in a genetically defined mouse model of lung adenocarcinoma. Endocr Relat Cancer 2008;15(2):475–83.PubMedCrossRefGoogle Scholar
  42. 42.
    Hershberger PA, Vasquez AC, Kanterewicz B, Land S, Siegfried JM, Nichols M. Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands. Cancer Res 2005;65(4):1598–605.PubMedCrossRefGoogle Scholar
  43. 43.
    Jarzynka MJ, Guo P, Bar-Joseph I, Hu B, Cheng SY. Estradiol and nicotine exposure enhances A549 bronchioloalveolar carcinoma xenograft growth in mice through the stimulation of angiogenesis. Int J Oncol 2006;28(2):337–44.PubMedGoogle Scholar
  44. 44.
    Pietras RJ, Marquez DC, Chen HW, Tsai E, Weinberg O, Fishbein M. Estrogen and growth factor receptor interactions in human breast and non-small cell lung cancer cells. Steroids 2005;70(5–7):372–81.PubMedCrossRefGoogle Scholar
  45. 45.
    Stabile LP, Lyker JS, Gubish CT, Zhang W, Grandis JR, Siegfried JM. Combined Targeting of the Estrogen Receptor and the Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer Shows Enhanced Anti-Proliferative Effects. Cancer Research 2005;65(4):1459–70.PubMedCrossRefGoogle Scholar
  46. 46.
    Marquez-Garban DC, Chen HW, Fishbein MC, Goodglick L, Pietras RJ. Estrogen receptor signaling pathways in human non-small cell lung cancer. Steroids 2007;72(2):135–43.PubMedCrossRefGoogle Scholar
  47. 47.
    Pedram A, Razandi M, Levin ER. Nature of functional estrogen receptors at the plasma membrane. Mol Endocrinol 2006;20(9):1996–2009.PubMedCrossRefGoogle Scholar
  48. 48.
    Zhang G, Liu X, Farkas AM, et al. Estrogen receptor beta functions through nongenomic mechanisms in lung cancer cells. Mol Endocrinol 2009;23(2):146–56.PubMedCrossRefGoogle Scholar
  49. 49.
    Mattingly KA, Ivanova MM, Riggs KA, Wickramasinghe NS, Barch MJ, Klinge CM. Estradiol stimulates transcription of nuclear respiratory factor-1 and increases mitochondrial biogenesis. Mol Endocrinol 2008;22(3):609–22.PubMedCrossRefGoogle Scholar
  50. 50.
    Yang SH, Sarkar SN, Liu R, et al. Estrogen receptor beta as a mitochondrial vulnerability factor. J Biol Chem 2009;284(14):9540–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Chen JQ, Eshete M, Alworth WL, Yager JD. Binding of MCF-7 cell mitochondrial proteins and recombinant human estrogen receptors alpha and beta to human mitochondrial DNA estrogen response elements. J Cell Biochem 2004;93(2):358–73.PubMedCrossRefGoogle Scholar
  52. 52.
    Klinge CM. Estrogenic control of mitochondrial function and biogenesis. J Cell Biochem 2008;105(6):1342–51.PubMedCrossRefGoogle Scholar
  53. 53.
    Simpkins JW, Yang SH, Sarkar SN, Pearce V. Estrogen actions on mitochondria--physiological and pathological implications. Mol Cell Endocrinol 2008;290(1–2):51–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Virbasius CA, Virbasius JV, Scarpulla RC. NRF-1, an activator involved in nuclear-mitochondrial interactions, utilizes a new DNA-binding domain conserved in a family of developmental regulators. Genes Dev 1993;7(12A):2431–45.PubMedCrossRefGoogle Scholar
  55. 55.
    Yang SH, Liu R, Perez EJ, et al. Mitochondrial localization of estrogen receptor beta. Proc Natl Acad Sci USA 2004;101(12):4130–5.PubMedCrossRefGoogle Scholar
  56. 56.
    Chen JQ, Delannoy M, Cooke C, Yager JD. Mitochondrial localization of ERalpha and ERbeta in human MCF7 cells. Am J Physiol Endocrinol Metab 2004;286(6):E1011-22.PubMedCrossRefGoogle Scholar
  57. 57.
    Milanesi L, Vasconsuelo A, de Boland AR, Boland R. Expression and subcellular distribution of native estrogen receptor beta in murine C2C12 cells and skeletal muscle tissue. Steroids 2009;74(6):489–97.PubMedCrossRefGoogle Scholar
  58. 58.
    Cammarata PR, Chu S, Moor A, Wang Z, Yang SH, Simpkins JW. Subcellular distribution of native estrogen receptor alpha and beta subtypes in cultured human lens epithelial cells. Exp Eye Res 2004;78(4):861–71.PubMedCrossRefGoogle Scholar
  59. 59.
    Pedram A, Razandi M, Wallace DC, Levin ER. Functional estrogen receptors in the mitochondria of breast cancer cells. Mol Biol Cell 2006;17(5):2125–37.PubMedCrossRefGoogle Scholar
  60. 60.
    Wu CT, Chang YL, Shih JY, Lee YC. The significance of estrogen receptor beta in 301 surgically treated non-small cell lung cancers. J Thorac Cardiovasc Surg 2005;130(4):979–86.PubMedCrossRefGoogle Scholar
  61. 61.
    Schwartz AG, Prysak GM, Murphy V, et al. Nuclear estrogen receptor beta in lung cancer: expression and survival differences by sex. Clin Cancer Res 2005;11(20):7280–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Kawai H, Ishii A, Washiya K, et al. Estrogen receptor alpha and beta are prognostic factors in non-small cell lung cancer. Clin Cancer Res 2005;11(14):5084–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Skov BG, Fischer BM, Pappot H. Oestrogen receptor beta over expression in males with non-small cell lung cancer is associated with better survival. Lung Cancer 2007.Google Scholar
  64. 64.
    Escande A, Pillon A, Servant N, et al. Evaluation of ligand selectivity using reporter cell lines stably expressing estrogen receptor alpha or beta. Biochem Pharmacol 2006;71(10):1459–69.PubMedCrossRefGoogle Scholar
  65. 65.
    Meyers MJ, Sun J, Carlson KE, Marriner GA, Katzenellenbogen BS, Katzenellenbogen JA. Estrogen receptor-beta potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J Med Chem 2001;44(24):4230–51.PubMedCrossRefGoogle Scholar
  66. 66.
    Stauffer SR, Coletta CJ, Tedesco R, Nishiguchi G, Carlson K, Sun J, Katzenellenbogen BS, Katzenellenbogen JA. Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists. J Medicinal Chemistry 2000;43(26):4934–47.CrossRefGoogle Scholar
  67. 67.
    Kato S, Endoh H, Masuhiro Y, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 1995;270(5241):1491–4.PubMedCrossRefGoogle Scholar
  68. 68.
    Curtis SW, Washburn T, Sewall C, et al. Physiological coupling of growth factor and steroid receptor signaling pathways: estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor. Proc Natl Acad Sci USA 1996;93(22):12626–30.PubMedCrossRefGoogle Scholar
  69. 69.
    Migliaccio A, Di Domenico M, Castoria G, et al. Steroid receptor regulation of epidermal growth factor signaling through Src in breast and prostate cancer cells: steroid antagonist action. Cancer Res 2005;65(22):10585–93.PubMedCrossRefGoogle Scholar
  70. 70.
    Razandi M, Pedram A, Park ST, Levin ER. Proximal events in signaling by plasma membrane estrogen receptors. J Biol Chem 2003;278(4):2701–12.PubMedCrossRefGoogle Scholar
  71. 71.
    Traynor AM, Schiller JH, Stabile LP, et al. Pilot study of gefitinib and fulvestrant in the treatment of post-menopausal women with advanced non-small cell lung cancer. Lung Cancer 2009;64(1):51–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Giovannini M, Belli C, Villa E, Gregorc V. Estrogen receptor (ER) and epidermal growth factor receptor (EGFR) as targets for dual lung cancer therapy: not just a case? J Thorac Oncol 2008;3(6):684–5.PubMedCrossRefGoogle Scholar
  73. 73.
    Miller WR, Hawkins RA, Forrest AP. Significance of aromatase activity in human breast cancer. Cancer Res 1982;42(8 Suppl):3365 s-8 s.PubMedGoogle Scholar
  74. 74.
    Bulun SE, Simpson ER. Breast cancer and expression of aromatase in breast adipose tissue. Trends Endocrinol Metab 1994;5(3):113–20.PubMedCrossRefGoogle Scholar
  75. 75.
    Yue W, Wang J, Savinov A, Brodie A. Effect of aromatase inhibitors on growth of mammary tumors in a nude mouse model. Cancer Res 1995;55(14):3073–7.PubMedGoogle Scholar
  76. 76.
    Buzdar AU, Coombes RC, Goss PE, Winer EP. Summary of aromatase inhibitor clinical trials in postmenopausal women with early breast cancer. Cancer 2008;112(3 Suppl):700–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Eisen A, Trudeau M, Shelley W, Messersmith H, Pritchard KI. Aromatase inhibitors in adjuvant therapy for hormone receptor positive breast cancer: a systematic review. Cancer Treat Rev 2008;34(2):157–74.PubMedCrossRefGoogle Scholar
  78. 78.
    Price T, Aitken J, Simpson ER. Relative expression of aromatase cytochrome P450 in human fetal tissues as determined by competitive polymerase chain reaction amplification. J Clin Endocrinol Metab 1992;74(4):879–83.PubMedCrossRefGoogle Scholar
  79. 79.
    Pezzi V, Mathis JM, Rainey WE, Carr BR. Profiling transcript levels for steroidogenic enzymes in fetal tissues. J Steroid Biochem Mol Biol 2003;87(2–3):181–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Weinberg OK, Marquez-Garban DC, Fishbein MC, et al. Aromatase inhibitors in human lung cancer therapy. Cancer Res 2005;65(24):11287–91.PubMedCrossRefGoogle Scholar
  81. 81.
    Mah V, Seligson DB, Li A, et al. Aromatase expression predicts survival in women with early-stage non small cell lung cancer. Cancer Res 2007;67(21):10484–90.PubMedCrossRefGoogle Scholar
  82. 82.
    Marquez-Garban DC, Chen HW, Goodglick L, Fishbein MC, Pietras RJ. Targeting aromatase and estrogen signaling in human non-small cell lung cancer. Ann N Y Acad Sci 2009;1155:194–205.PubMedCrossRefGoogle Scholar
  83. 83.
    Niikawa H, Suzuki T, Miki Y, et al. Intratumoral estrogens and estrogen receptors in human non-small cell lung carcinoma. Clin Cancer Res 2008;14(14):4417–26.PubMedCrossRefGoogle Scholar
  84. 84.
    Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350(11):1081–92.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • P. A. Hershberger
    • 1
  • J. M. Siegfried
    • 2
  1. 1.Department of PharmacologyUniversity of PittsburghPittsburghUSA
  2. 2.Thoracic Malignancies Program, Department of PharmacologyUniversity of Pittsburgh Cancer InstitutePittsburghUSA

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