Expression and regulation mechanisms of Sonic Hedgehog in breast cancer

Abstract

Sonic Hedgehog (Shh) plays an essential role in vertebrate organogenesis as well as the development of some cancers, including breast cancer. The aim of the present study was to characterize more precisely its role in breast carcinogenesis and elucidate its regulation mechanisms. The expression of Shh was investigated in 97 breast carcinomas and 22 paired non-tumorous tissues (distant from the primary tumor) by immunohistochemistry and in four breast cell lines by Western blotting. We also analyzed the methylation status of the Shh gene with methylation-specific PCR and assessed whether nuclear factor-kappa B (NF-jB) and Gli1 were expressed in breast tissues by immunohistochemistry. Our results showed that Shh protein expression in breast carcinomas was significant higher than that in normal breast tissues (P < 0.01). The upregulation of Shh in breast carcinomas was correlated significantly with early clinical stage (P < 0.05). In addition, we found a substantial increase in Shh expression at both the mRNA and protein levels in several human breast carcinoma cell lines. The expression level of nuclear Gli1 was positively associated with the expression level of Shh in breast tissues (P < 0.001). Promoter region hypomethylation (43/61, 70.5%) was frequently observed in breast carcinomas and significantly associated with Shh up-regulation (P < 0.05). The DNA methyltransferase inhibitor 5-azacytidine (5-Aza) reduced the methylation of Shh promoter and increased the expression of Shh protein in MDA-MB-435 and MCF-10A cells. Furthermore, most of the breast carcinoma cases with Shh up-regulation had increased expression of NF-jB (35/49, 71.4%; P < 0.001). Taken together, these observations suggest that Shh overexpression is a critical event in breast carcinogenesis, and Shh promoter hypomethylation and NF-jB up-regulation are responsible for the up-regulation of Shh. (Cancer Sci 2010; 101: 927-933)

The Utility of Hedgehog Signaling Pathway Inhibition for Cancer

“…In this series, elevated expression level of SMO correlated with the presence of nodal disease, implicating its role in metastasis and disease progression [42]. Autocrine activation of the Hh pathway has also been shown in breast cancer, both in cell lines and tumoral tissue studies [43][44][45]. In a study by Kubo et al, overexpression of SHH and GLI1 was detected in virtually all of the 52 breast cancer specimens examined [43].…”

“…In a study by Kubo et al, overexpression of SHH and GLI1 was detected in virtually all of the 52 breast cancer specimens examined [43]. In another series, the overexpression of SHH in breast cancers was shown to be secondary to hypomethylation of the ligand promoter as well as NF-B upregulation [45]. Furthermore, akin to studies in lung cancers, inhibition of Hh pathway using cyclopamine led to suppression of proliferation in breast cancer cell lines in a dose-dependent manner [43].…”

B4GALT1 gene knockdown inhibits the hedgehog pathway and reverses multidrug resistance in the human leukemia K562/adriamycin‐resistant cell line

“…Transcriptional activation occurs through the glioma-associated oncogene homolog (GLI) proteins family, resulting in activation of target genes (19). Aberrant activation of the Hh pathway has been linked to multiple types of human cancer, characterized by high expression levels of Shh, ptch, Smo, and GLI-1 (20)(21)(22)(23). They are also detectable in several leukemic cell lines with drug resistance.…”

Immunobiology and signaling pathways of cancer stem cells: implication for cancer therapy

“…SMO is expressed at higher amounts in Ductal carcinoma in situ and invasive ductal carcinoma (IDC), where its constitutive activation in mouse mammary glands brings about ductal dysplasia (Moraes et al 2009). Immunohistological identification of SHH was higher in breast cancers comparing with normal tissue (Cui et al 2010). Moreover, the Hh signaling pathway was discovered to be activated in the CSC-enriched CD44…”

“…Brain cancers have inactivating PTCH1 mutations (Hahn et al 1996), GLI1 was highly expressed in 26 % of primary GBMs and 57 % of cell lines (Bar et al 2007) and GLI1 shRNA brought about a critical diminishing in glioma development in vitro (Bao et al 2006) Breast cancers showed loss of PTCH1 and expansion in the GLI1 region (Naylor et al 2005), immunohistological identification of SHH was higher in breast cancers (Cui et al 2010), Moreover, the Hh signaling pathway is activated in breast CSC (Tanaka et al 2009) Hh signaling components are actually activated in advanced human colon cancer cells and their CSCs (Varnat et al 2010), GLI1 expression was increased in colon CSCs (Varnat et al 2010). Hence, metastatic colon cancers could conceivably be treated by blocking Hh signaling (Varnat et al 2010) ensnared a vital role for Notch signaling in the selfrenewal and maintenance of CSCs (Purow et al 2005).…”