title: In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors.
abstract: Aberrant Hedgehog (Hh)/glioma-associated oncogene (GLI) signaling has been implicated in cancer progression. Here, we analyzed GLI1, Sonic Hedgehog (Shh) and NF-κB expression in 51 breast cancer (ductal carcinoma) tissues using immunohistochemistry. We found a positive correlation between nuclear GLI1 expression and tumor grade in ductal carcinoma cases. Cytoplasmic Shh staining significantly correlated with a lower tumor grade. Next, the in vitro effects of two Hh signaling pathway inhibitors on breast cancer cell lines were evaluated using the Smoothened (SMO) antagonist GDC-0449 and the direct GLI1 inhibitor GANT-61. GDC-0449 and GANT-61 exhibited the following effects: a) inhibited breast cancer cell survival; b) induced apoptosis; c) inhibited Hh pathway activity by decreasing the mRNA expression levels of GLI1 and Ptch and inhibiting the nuclear translocation of GLI1; d) increased/decreased EGFR and ErbB2 protein expression, reduced p21-Ras and ERK1/ERK2 MAPK activities and inhibited AKT activation; and e) decreased the nuclear translocation of NF-κB. However, GANT-61 exerted these effects more effectively than GDC-0449. The in vivo antitumor activities of GDC-0449 and GANT-61 were analyzed in BALB/c mice that were subcutaneously inoculated with mouse breast cancer (TUBO) cells. GDC-0449 and GANT-61 suppressed tumor growth of TUBO cells in BALB/c mice to different extents. These findings suggest that targeting the Hh pathway using antagonists that act downstream of SMO is a more efficient strategy than using antagonists that act upstream of SMO for interrupting Hh signaling in breast cancer.
authors: Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors: Monica
authors: M
authors: Benvenuto
authors: Department of Experimental Medicine, University of Rome "Sapienza", Rome, Italy.
authors: Laura
authors: L
authors: Masuelli
authors: Department of Experimental Medicine, University of Rome "Sapienza", Rome, Italy.
authors: Enrico
authors: E
authors: De Smaele
authors: Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors: Massimo
authors: M
authors: Fantini
authors: Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy.|Department of Molecular Medicine, University of Rome "Sapienza", Rome, Italy.
authors: Rosanna
authors: R
authors: Mattera
authors: Department of Molecular Medicine, University of Rome "Sapienza", Rome, Italy.
authors: Danilo
authors: D
authors: Cucchi
authors: Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
authors: Elena
authors: E
authors: Bonanno
authors: Department of Experimental Medicine, University of Rome "Sapienza", Rome, Italy.
authors: Enrica
authors: E
authors: Di Stefano
authors: Department of Physical Education, Human Sciences and Health, University of Rome "Foro Italico", Rome, Italy.
authors: Giovanni Vanni
authors: GV
authors: Frajese
authors: Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
authors: Augusto
authors: A
authors: Orlandi
authors: Department of Molecular Medicine, University of Rome "Sapienza", Rome, Italy.
authors: Isabella
authors: I
authors: Screpanti
authors: Department of Molecular Medicine, University of Rome "Sapienza", Rome, Italy.
authors: Alberto
authors: A
authors: Gulino
authors: Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors: Andrea
authors: A
authors: Modesti
authors: Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors: Roberto
authors: R
authors: Bei
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000813:Anilides / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D044584:Carcinoma, Ductal / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000096:biosynthesis; D000072081:Patched-1 Receptor / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor / Q000037:antagonists & inhibitors*; D000071676:Zinc Finger Protein GLI1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D000813:Anilides; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D053823:Hedgehog Proteins; D016328:NF-kappa B; D000072081:Patched-1 Receptor; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D000072086:Smoothened Receptor; D000071676:Zinc Finger Protein GLI1; C551027:GANT 61; C538724:HhAntag691; C000606236:PTCH1 protein, human; C509239:SHH protein, human; C491023:SMO protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: Hedgehog/GLI pathway; breast cancer; inhibitors; tumor growth; tumor model