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
