Hedgehog Related Protein Expression in Breast Cancer: Gli-2 Is Associated with Poor Overall Survival

Background: The hedgehog (Hh) signaling pathway is known to play a critical role in various malignancies, but its clinicopathologic role in breast cancer is yet to be established. Methods: Tissue microarray blocks from 334 cases of breast cancer were prepared. The expression of six Hh signaling proteins including sonic hedgehog (Shh), patched (Ptch), smoothened (Smo), and the glioma-associated oncogene (Gli)-1, Gli-2, and Gli-3 were analyzed immunohistochemically. Results: The expression of Hh signaling proteins was significantly correlated with some prognostic factors including the correlation of lymph node metastasis with the expression of Shh (p = 0.001) and Ptch (p = 0.064), the correlation of the stages with Shh and Gli-3 expression (p = 0.007 and p = 0.024, respectively), the correlation of the nuclear grade with the Smo (p= 0.004) and Gli-3 (p=0.000), and the correlation of the histologic grade with the Ptch (p = 0.016), Smo (p = 0.007), and Gli-3 (p= 0.000). The Shh, Ptch, Smo, Gli-1, and Gli-2 expression was significantly different between the phenotypes (p= 0.000, pm 0.001, p= 0.004, p= 0.039, and p= 0.031, respectively). Gli-2 expression was correlated with a worse overall survival outcome (p=0.012). Conclusions: Hh pathway activation is correlated with a more aggressive clinical behavior in breast carcinomas. The comparison of phenotypes suggested that the Hh pathway may be a useful therapeutic target for breast carcinoma. Patients with Gli-2 expression had a significantly lower overall survival rate and, therefore, it showed promise as a prognostic marker.