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
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Monica Benvenuto1,*, Laura Masuelli2,*, Enrico De Smaele2, Massimo Fantini1, Rosanna Mattera1,3, Danilo Cucchi3, Elena Bonanno4, Enrica Di Stefano2, Giovanni Vanni Frajese5, Augusto Orlandi4, Isabella Screpanti3, Alberto Gulino3, Andrea Modesti1 and Roberto Bei1
1 Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Rome, Italy
2 Department of Experimental Medicine, University of Rome “Sapienza”, Rome, Italy
3 Department of Molecular Medicine, University of Rome “Sapienza”, Rome, Italy
4 Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
5 Department of Physical Education, Human Sciences and Health, University of Rome “Foro Italico”, Rome, Italy
* These authors have contributed equally to this work
Roberto Bei, email:
Keywords: breast cancer, Hedgehog/GLI pathway, inhibitors, tumor growth, tumor model
Received: October 14, 2015 Accepted: January 18, 2016 Published: January 28, 2016
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.
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