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Current Breast Cancer Reports
Erschienen in: Current Breast Cancer Reports 1/2011

01.03.2011

Hedgehog Pathway Inhibitors: Potential Applications in Breast Cancer

verfasst von: Yee Hong Chia, Cynthia X. Ma

Erschienen in: Current Breast Cancer Reports | Ausgabe 1/2011

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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.
Literatur
1.
Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980;287:795–801.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
4.
Marigo V, Davey RA, Zuo Y, Cunningham JM, Tabin CJ. Biochemical evidence that patched is the Hedgehog receptor. Nature 1996;384:176–9.CrossRefPubMed
5.
Chuang PT, McMahon AP. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 1999;397:617–21.CrossRefPubMed
6.
Taipale J, Cooper MK, Maiti T, Beachy PA. Patched acts catalytically to suppress the activity of Smoothened. Nature 2002;418:892–7.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
9.
Rohatgi R, Milenkovic L, Scott MP. Patched1 regulates hedgehog signaling at the primary cilium. Science 2007;317:372–6.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
14.
15.
Roessler E, Belloni E, Gaudenz K, et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 1996;14:357–60.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
18.
Briscoe J, Therond P. Hedgehog signaling: from the Drosophila cuticle to anti-cancer drugs. Dev Cell 2005;8:143–51.CrossRefPubMed
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.PubMed
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.CrossRefPubMed
21.
Raffel C, Jenkins RB, Frederick L, et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res 1997;57:842–5.PubMed
22.
Berman DM, Karhadkar SS, Hallahan AR, et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 2002;297:1559–61.CrossRefPubMed
23.
Taylor MD, Liu L, Raffel C, et al. Mutations in SUFU predispose to medulloblastoma. Nat Genet 2002;31:306–10.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.PubMed
30.
Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for hedgehog signalling in cancer. Nature 2008;455:406–10.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
34.
Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004;431:707–12.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.PubMed
38.
Fiaschi M, Rozell B, Bergstrom A, Toftgard R. Development of mammary tumors by conditional expression of GLI1. Cancer Res 2009;69:4810–7.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.PubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
46.
Katano M. Hedgehog signaling pathway as a therapeutic target in breast cancer. Cancer Lett 2005;227:99–104.CrossRefPubMed
47.
Xuan Y, Lin Z. Expression of Indian Hedgehog signaling molecules in breast cancer. J Cancer Res Clin Oncol 2009;135:235–40.CrossRefPubMed
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.PubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.PubMed
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.CrossRefPubMed
53.
Eyler CE, Rich JN. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol 2008;26:2839–45.CrossRefPubMed
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.CrossRefPubMed
55.
Hanby AM, Hughes TA. In situ and invasive lobular neoplasia of the breast. Histopathology 2008;52:58–66.CrossRefPubMed
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.PubMed
57.
Meng X, Poon R, Zhang X, et al. Suppressor of fused negatively regulates beta-catenin signaling. J Biol Chem 2001;276:40113–9.CrossRefPubMed
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.CrossRefPubMed
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. CrossRef
60.
61.
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.CrossRefPubMed
63.
64.
65.
66.
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.CrossRefPubMed
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.CrossRefPubMed
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. CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
72.
Lauth M, Toftgard R. Non-canonical activation of GLI transcription factors: implications for targeted anti-cancer therapy. Cell Cycle 2007;6:2458–63.CrossRefPubMed
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.CrossRefPubMed
Metadaten
Titel
Hedgehog Pathway Inhibitors: Potential Applications in Breast Cancer
verfasst von
Yee Hong Chia
Cynthia X. Ma
Publikationsdatum
01.03.2011
Verlag
Current Science Inc.
Erschienen in
Current Breast Cancer Reports / Ausgabe 1/2011
Print ISSN: 1943-4588
Elektronische ISSN: 1943-4596
DOI
https://doi.org/10.1007/s12609-010-0031-3

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