Prognostic significance of hedgehog signaling network‐related gene expression in breast cancer patients

Abstract

Breast cancer continues to be a serious public health problem. The role of the hedgehog pathway in normal development of the mammary gland as well as in carcinogenesis and progression of breast cancer is the subject of intense investigation, revealing functional interactions with cell surface heparan sulfate. Nevertheless, its influence on breast cancer prognosis, and its relation to specific sulfation motifs in heparan sulfate have only been poorly studied in large patient cohorts. Using the public database KMplotter that includes gene expression and survival data of 3951 patients, we found that the higher expression of SHH, HHAT, PTCH1, GLI1, GLI2, and GLI3 positively influences breast cancer prognosis. Stratifying patients according to the expression of hormone receptors, histological grade, lymph node metastasis, and systemic therapy, we observed that GLI1, GLI2, and GLI3 expression, as well as coexpression of SHH and ELP1 were associated with worse relapse-free survival in patients with HER2-positive tumors. Moreover, GLI1 expression in progesterone receptor-negative tumors and GLI3 expression in grade 3 tumors correlated with poor prognosis. SHH, in a panel of cell lines representing different breast cancer subtypes, and HHAT, PTCH1, GLI1, GLI2, and GLI3 were mostly expressed in cell lines classified as HER2-positive and basal-like.

GREB1L overexpression associates with good clinical outcomes in breast cancer

“…They found that without considering subgroup of BRCA, the high expression of SHH, HHAT, GLI1, GLI2, GLI3 and PTCH1 were associated with better RFS. High expression of HHAT is associated with better OS [39]. In our study, we found that GREB1L was also a related gene of HH signaling pathway, its high expression indicated better OS and RFS of BRCA.…”

Prognostic impact of the glypican family of heparan sulfate proteoglycans on the survival of breast cancer patients

“…Sonic hedgehog (SHH) release is controlled by glypicans, which stimulate its proteolytic processing into bioactive sonic hedgehog. Genes related to the hedgehog pathway have been shown to be associated with better survival of breast cancer patients (Kuehn et al 2021 ). Protein patched homolog 1 (PTCH1) serves as a receptor for SHH and associates with the smoothened protein (SMO) to transduce the hedgehog’s protein signals (Filmus and Capurro 2014 ).…”

The Cell Surface Heparan Sulfate Proteoglycan Syndecan-3 Promotes Ovarian Cancer Pathogenesis

“…Since heparan sulfate proteoglycans modulate numerous signaling pathways relevant to cancer stem cell properties [ 7 , 25 ], we next used qPCR analysis to investigate the impact of SDC3 depletion on the expression of constituents of the notch pathway ( Notch1 , Hes1 , Hey2 , Msi1 , Msi2 ), hedgehog signaling ( SHH , PTCH1 , Gli1-3 , Robo1 ), Wnt signaling ( Wnt3A , Wnt 5A , SFRP1 , TCF7L1 , TCF7L2 ), and markers of epithelial-to-mesenchymal transition (EMT) ( Twist , Snail , CDH1 , Vimentin , ZEB1 ) by SKOV3 and CAOV3 cells. Moreover, we evaluated the expression of the other members of the syndecan family ( SDC1 , SDC2 , SDC4 ) for potential compensatory expression changes, and assessed the expression of the proto-oncogene tyrosine-protein kinase Src, previously described to interact with Sdc3 [ 26 ].…”

“…In line with our analysis, various studies show the correlation between heparan sulfate proteoglycans and stemness-related signaling [ 7 , 22 , 39 , 50 ]. For example, increased 3-O-sulfation of heparan sulfate enhances expression of the Wnt-dependent transcription factor TFF4/TCF7L2 and 3D sphere formation in breast cancer cells and results in differential expression of constituents of the prognostically relevant hedgehog pathway [ 21 , 25 , 51 ]. Altered 3-o-sulfation of heparan sulfate has also been shown to sensitize ovarian carcinoma to oncogenic signals and to be a predictor of prognosis [ 50 ].…”