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Hedgehog Pathway Inhibitors: Potential Applications in Breast Cancer

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Abstract

The Hedgehog (Hh) signaling pathway is a developmental pathway with important roles in embryogenesis, epithelial-mesenchymal transition, stem/progenitor cell renewal, and tissue regeneration and repair. Dysregulated Hh signaling is implicated in 25% of human cancers, including breast cancer. Mutations within elements of the Hh signaling pathway leading to ligand-independent activation do not appear to be widespread in breast cancer. However, overexpression of the Hh ligand and Hh target genes has been reported in breast cancer, suggesting a ligand-dependent mechanism for Hh pathway activation in breast carcinogenesis. Small molecule antagonists of the Hh pathway are under clinical development and may present novel therapeutic options for breast cancer.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980;287:795–801.

    Article  CAS  PubMed  Google Scholar 

  2. Echelard Y, Epstein DJ, St-Jacques B, et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 1993;75:1417–30.

    Article  CAS  PubMed  Google Scholar 

  3. Burke R, Nellen D, Bellotto M, et al. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell 1999;99:803–15.

    Article  CAS  PubMed  Google Scholar 

  4. Marigo V, Davey RA, Zuo Y, Cunningham JM, Tabin CJ. Biochemical evidence that patched is the Hedgehog receptor. Nature 1996;384:176–9.

    Article  CAS  PubMed  Google Scholar 

  5. Chuang PT, McMahon AP. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 1999;397:617–21.

    Article  CAS  PubMed  Google Scholar 

  6. Taipale J, Cooper MK, Maiti T, Beachy PA. Patched acts catalytically to suppress the activity of Smoothened. Nature 2002;418:892–7.

    Article  CAS  PubMed  Google Scholar 

  7. Huangfu D, Liu A, Rakeman AS, Murcia NS, Niswander L, Anderson KV. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 2003;426:83–7.

    Article  CAS  PubMed  Google Scholar 

  8. Carpenter D, Stone DM, Brush J, et al. Characterization of two patched receptors for the vertebrate hedgehog protein family. Proc Natl Acad Sci USA 1998;95:13630–4.

    Article  CAS  PubMed  Google Scholar 

  9. Rohatgi R, Milenkovic L, Scott MP. Patched1 regulates hedgehog signaling at the primary cilium. Science 2007;317:372–6.

    Article  CAS  PubMed  Google Scholar 

  10. Kinzler KW, Bigner SH, Bigner DD, et al. Identification of an amplified, highly expressed gene in a human glioma. Science 1987;236:70–3.

    Article  CAS  PubMed  Google Scholar 

  11. Wang B, Li Y. Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proc Natl Acad Sci USA 2006;103:33–8.

    Article  CAS  PubMed  Google Scholar 

  12. Tempe D, Casas M, Karaz S, Blanchet-Tournier MF, Concordet JP. Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP. Mol Cell Biol 2006;26:4316–26.

    Article  CAS  PubMed  Google Scholar 

  13. Wang B, Fallon JF, Beachy PA. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 2000;100:423–34.

    Article  CAS  PubMed  Google Scholar 

  14. Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev 2008;22:2454–72.

    Article  CAS  PubMed  Google Scholar 

  15. Roessler E, Belloni E, Gaudenz K, et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 1996;14:357–60.

    Article  CAS  PubMed  Google Scholar 

  16. Keeler RF, Binns W. Teratogenic compounds of Veratrum californicum (Durand). V. Comparison of cyclopian effects of steroidal alkaloids from the plant and structurally related compounds from other sources. Teratology 1968;1:5–10.

    Article  CAS  PubMed  Google Scholar 

  17. Taipale J, Chen JK, Cooper MK, et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 2000;406:1005–9.

    Article  CAS  PubMed  Google Scholar 

  18. Briscoe J, Therond P. Hedgehog signaling: from the Drosophila cuticle to anti-cancer drugs. Dev Cell 2005;8:143–51.

    Article  CAS  PubMed  Google Scholar 

  19. Unden AB, Holmberg E, Lundh-Rozell B, et al. Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation. Cancer Res 1996;56:4562–5.

    CAS  PubMed  Google Scholar 

  20. Reifenberger J, Wolter M, Knobbe CB, et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol 2005;152:43–51.

    Article  CAS  PubMed  Google Scholar 

  21. Raffel C, Jenkins RB, Frederick L, et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res 1997;57:842–5.

    CAS  PubMed  Google Scholar 

  22. Berman DM, Karhadkar SS, Hallahan AR, et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 2002;297:1559–61.

    Article  CAS  PubMed  Google Scholar 

  23. Taylor MD, Liu L, Raffel C, et al. Mutations in SUFU predispose to medulloblastoma. Nat Genet 2002;31:306–10.

    Article  CAS  PubMed  Google Scholar 

  24. Tostar U, Malm CJ, Meis-Kindblom JM, Kindblom LG, Toftgard R, Unden AB. Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J Pathol 2006;208:17–25.

    Article  CAS  PubMed  Google Scholar 

  25. Wolf I, Bose S, Desmond JC, et al. Unmasking of epigenetically silenced genes reveals DNA promoter methylation and reduced expression of PTCH in breast cancer. Breast Cancer Res Treat 2007;105:139–55.

    Article  CAS  PubMed  Google Scholar 

  26. Tada M, Kanai F, Tanaka Y, et al. Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma. Clin Cancer Res 2008;14:3768–76.

    Article  CAS  PubMed  Google Scholar 

  27. Taniguchi H, Yamamoto H, Akutsu N, et al. Transcriptional silencing of hedgehog-interacting protein by CpG hypermethylation and chromatic structure in human gastrointestinal cancer. J Pathol 2007;213:131–9.

    Article  CAS  PubMed  Google Scholar 

  28. Martin ST, Sato N, Dhara S, et al. Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms. Cancer Biol Ther 2005;4:728–33.

    Article  CAS  PubMed  Google Scholar 

  29. Chun SG, Zhou W, Yee NS. Combined targeting of histone deacetylases and hedgehog signaling enhances cytoxicity in pancreatic cancer. Cancer Biol Ther 2009;8:1328–39.

    CAS  PubMed  Google Scholar 

  30. Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for hedgehog signalling in cancer. Nature 2008;455:406–10.

    Article  CAS  PubMed  Google Scholar 

  31. Dierks C, Grbic J, Zirlik K, et al. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med 2007;13:944–51.

    Article  CAS  PubMed  Google Scholar 

  32. Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA, Baylin SB. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003;422:313–7.

    Article  CAS  PubMed  Google Scholar 

  33. Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003;425:846–51.

    Article  CAS  PubMed  Google Scholar 

  34. Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004;431:707–12.

    Article  CAS  PubMed  Google Scholar 

  35. Tian H, Callahan CA, DuPree KJ, et al. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci USA 2009;106:4254–9.

    Article  CAS  PubMed  Google Scholar 

  36. Moraes RC, Zhang X, Harrington N, et al. Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia. Development 2007;134:1231–42.

    Article  CAS  PubMed  Google Scholar 

  37. Lewis MT, Ross S, Strickland PA, et al. Defects in mouse mammary gland development caused by conditional haploinsufficiency of Patched-1. Development 1999;126:5181–93.

    CAS  PubMed  Google Scholar 

  38. Fiaschi M, Rozell B, Bergstrom A, Toftgard R. Development of mammary tumors by conditional expression of GLI1. Cancer Res 2009;69:4810–7.

    Article  CAS  PubMed  Google Scholar 

  39. Lewis MT, Ross S, Strickland PA, et al. The Gli2 transcription factor is required for normal mouse mammary gland development. Dev Biol 2001;238:133–44.

    Article  CAS  PubMed  Google Scholar 

  40. Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein EH, Jr., Scott MP. Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 1997;276:817–21.

    Article  CAS  PubMed  Google Scholar 

  41. Xie J, Johnson RL, Zhang X, et al. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res 1997;57:2369–72.

    CAS  PubMed  Google Scholar 

  42. Vorechovsky I, Benediktsson KP, Toftgard R. The patched/hedgehog/smoothened signalling pathway in human breast cancer: no evidence for H133Y SHH, PTCH and SMO mutations. Eur J Cancer 1999;35:711–3.

    Article  CAS  PubMed  Google Scholar 

  43. Naylor TL, Greshock J, Wang Y, et al. High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization. Breast Cancer Res 2005;7:R1186–98.

    Article  CAS  PubMed  Google Scholar 

  44. Chang-Claude J, Dunning A, Schnitzbauer U, et al. The patched polymorphism Pro1315Leu (C3944T) may modulate the association between use of oral contraceptives and breast cancer risk. Int J Cancer 2003;103:779–83.

    Article  CAS  PubMed  Google Scholar 

  45. Kubo M, Nakamura M, Tasaki A, et al. Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res 2004;64:6071-4.

    Article  CAS  PubMed  Google Scholar 

  46. Katano M. Hedgehog signaling pathway as a therapeutic target in breast cancer. Cancer Lett 2005;227:99–104.

    Article  CAS  PubMed  Google Scholar 

  47. Xuan Y, Lin Z. Expression of Indian Hedgehog signaling molecules in breast cancer. J Cancer Res Clin Oncol 2009;135:235–40.

    Article  CAS  PubMed  Google Scholar 

  48. Hu Z, Bonifas JM, Aragon G, et al. Evidence for lack of enhanced hedgehog target gene expression in common extracutaneous tumors. Cancer Res 2003;63:923–8.

    CAS  PubMed  Google Scholar 

  49. Mukherjee S, Frolova N, Sadlonova A, et al. Hedgehog signaling and response to cyclopamine differ in epithelial and stromal cells in benign breast and breast cancer. Cancer Biol Ther 2006;5:674–83.

    Article  CAS  PubMed  Google Scholar 

  50. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003;100:3983–8.

    Article  CAS  PubMed  Google Scholar 

  51. Tanaka H, Nakamura M, Kameda C, et al. The Hedgehog signaling pathway plays an essential role in maintaining the CD44+CD24-/low subpopulation and the side population of breast cancer cells. Anticancer Res 2009;29:2147–57.

    CAS  PubMed  Google Scholar 

  52. Liu SL, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Research 2006;66:6063–71.

    Article  CAS  PubMed  Google Scholar 

  53. Eyler CE, Rich JN. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol 2008;26:2839–45.

    Article  CAS  PubMed  Google Scholar 

  54. Li X, Deng W, Lobo-Ruppert SM, Ruppert JM. Gli1 acts through Snail and E-cadherin to promote nuclear signaling by beta-catenin. Oncogene 2007;26:4489–98.

    Article  CAS  PubMed  Google Scholar 

  55. Hanby AM, Hughes TA. In situ and invasive lobular neoplasia of the breast. Histopathology 2008;52:58–66.

    Article  CAS  PubMed  Google Scholar 

  56. Li X, Deng W, Nail CD, et al. Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation. Oncogene 2006;25:609–21.

    CAS  PubMed  Google Scholar 

  57. Meng X, Poon R, Zhang X, et al. Suppressor of fused negatively regulates beta-catenin signaling. J Biol Chem 2001;276:40113–9.

    Article  CAS  PubMed  Google Scholar 

  58. Lipinski RJ, Hutson PR, Hannam PW, et al. Dose- and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the hedgehog signaling antagonist cyclopamine in the mouse. Toxicol Sci 2008;104:189–97.

    Article  CAS  PubMed  Google Scholar 

  59. • Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 2009;361:1164–72. This is the first report of a clinical trial in which a Hedgehog inhibitor, GDC-0449, was demonstrated to have efficacy in a malignancy driven by aberrant Hedgehog signaling.

    Article  Google Scholar 

  60. GDC-0449 and RO4929097 in Treating Women With Advanced Breast Cancer. Available at http://clinicaltrials.gov/ct2/show/NCT01071564?term=gdc-0449&rank=20. Accessed September 29, 2010.

  61. Curis Announces Genentech’s Phase II Clinical Trial Results of GDC-0449 in Combination with Avastin(R) and Chemotherapy in First-Line Metastatic Colorectal Cancer. Available at http://phx.corporate-ir.net/phoenix.zhtml?c=123198&p=irol-newsArticle&ID=1438731&highlight=. Accessed September 29, 2010.

  62. Tremblay MR, Lescarbeau A, Grogan MJ, et al. Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). J Med Chem 2009;52:4400–18.

    Article  CAS  PubMed  Google Scholar 

  63. A Study Of PF-04449913 In Select Hematologic Malignancies Or With Dasatinib In Chronic Myeloid Leukemia (CML). Available at http://clinicaltrials.gov/ct2/show/NCT00953758. Accessed September 29, 2010.

  64. A Study of BMS-833923 With Cisplatin and Capecitabine in Inoperable, Metastatic Gastric, Gastroesophageal, or Esophageal Adenocarcinomas. Available at http://clinicaltrials.gov/ct2/show/NCT00909402?term=xl139&rank=2. Accessed September 29, 2010.

  65. Dose Finding and Safety of Oral LDE225 in Patients With Advanced Solid Tumors. Available at http://clinicaltrials.gov/ct2/show/NCT00880308?term=hedgehog&rank=32. Accessed September 29, 2010.

  66. A Dose Finding and Safety Study of Oral LEQ506 in Patients With Advanced Solid Tumors. Available at http://clinicaltrials.gov/ct2/show/NCT01106508?term=leq506&rank=1. Accessed September 29, 2010.

  67. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324:1457–61.

    Article  CAS  PubMed  Google Scholar 

  68. Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 2009;361:1173–8.

    Article  CAS  PubMed  Google Scholar 

  69. • Yauch RL, Dijkgraaf GJ, Alicke B, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 2009;326:572–4. Yauch et al. reported on a patient who rapidly developed resistance to GDC-0449. They discovered that a Smoothened mutation was the underlying explanation, highlighting the need to develop inhibitors directed towards other targets in the pathway.

    Article  CAS  PubMed  Google Scholar 

  70. Stanton BZ, Peng LF, Maloof N, et al. A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat Chem Biol 2009;5:154–6.

    Article  CAS  PubMed  Google Scholar 

  71. Edison RJ, Muenke M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet A 2004;131:287–98.

    Article  PubMed  Google Scholar 

  72. Lauth M, Toftgard R. Non-canonical activation of GLI transcription factors: implications for targeted anti-cancer therapy. Cell Cycle 2007;6:2458–63.

    Article  CAS  PubMed  Google Scholar 

  73. Lauth M, Bergstrom A, Shimokawa T, Toftgard R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci USA 2007;104:8455–60.

    Article  CAS  PubMed  Google Scholar 

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Yee Hong Chia reports no potential conflict of interest relevant to this article. Cynthia X. Ma reports no potential conflict of interest relevant to this article.

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  1. Department of Medicine, Division of Oncology, Washington University, 660 South Euclid Ave, St Louis, MO, 63110, USA

    Yee Hong Chia & Cynthia X. Ma

  2. Siteman Cancer Center, Washington University, 660 South Euclid Ave, St Louis, MO, 63110, USA

    Cynthia X. Ma

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  1. Yee Hong Chia
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Correspondence to Cynthia X. Ma.

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Chia, Y.H., Ma, C.X. Hedgehog Pathway Inhibitors: Potential Applications in Breast Cancer. Curr Breast Cancer Rep 3, 15–23 (2011). https://doi.org/10.1007/s12609-010-0031-3

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