Oncotarget

Research Papers:

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

Monica Benvenuto, Laura Masuelli, Enrico De Smaele, Massimo Fantini, Rosanna Mattera, Danilo Cucchi, Elena Bonanno, Enrica Di Stefano, Giovanni Vanni Frajese, Augusto Orlandi, Isabella Screpanti, Alberto Gulino, Andrea Modesti and Roberto Bei _

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Oncotarget. 2016; 7:9250-9270. https://doi.org/10.18632/oncotarget.7062

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Abstract

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

Correspondence to:

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

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.


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