Overexpression of Hedgehog signaling molecules and its involvement in triple-negative breast cancer

Abstract

Abstract. The purpose of this study was to investigate the activation of Hedgehog (Hh) signaling molecules and its involvement in triple-negative breast cancer (TNBC). A total of 123 cases of paraffin blocks, including 83 cases of primary breast carcinoma, 30 cases of mammary hyperplasia and 10 cases of normal breast tissue, were immunohistochemically analyzed for Sonic Hedgehog (SHH), Patched-1 (PTCH1), Smoothened (SMO) and glioma-associated oncogene homoglog 1 (GLI1) expression. The expression of SMO and GLI1 in TNBC was significantly increased in comparison to non-triple-negative breast cancer (nTNBC). GLI1 expression manifested an inverse association with the estrogen receptor. The levels of GLI1 expression were increased in lymph nodepositive cases. The expression of SHH and SMO was increased in high histological grades. Furthermore, the expression of SMO and GLI1 was correlated with superior tumor stage. The expression of SHH, SMO and GLI1 was significantly increased in breast cancer and mammary hyperplasia. PTCH1 expression was significantly decreased in breast cancer compared to mammary hyperplasia and normal breast tissue. For the first time, clinical evidence has been provided in support of significant roles of Hh signaling in TNBC. Hh signaling is involved in breast ductal changes and malignant transformation. Measures to inhibit Hh activity may improve the prognosis of TNBC patients.

High expression of Sonic Hedgehog signaling pathway genes indicates a risk of recurrence of breast carcinoma

“…SMOH encoding of a transmembrane protein acting in a receptor complex was affected by PTCH-1 15,16,18,23. Tao et al studied patients having triple-negative breast cancer by immunohistochemical analysis of factors in the SHH pathway 26. They observed that expression of PTCH-1 was significantly decreased in breast cancer compared with mammary hyperplasia.…”

The Potential Role of Hedgehog Signaling in the Luminal/Basal Phenotype of Breast Epithelia and in Breast Cancer Invasion and Metastasis

“…Further evidence for differing Hh patterns within the different breast cancer subgroups was illustrated by the finding of Gli-1 and Smo overexpression in TN breast cancer cases and a positive correlation with increased tumor stage. This was offset by an inverse correlation with estrogen receptor (ER) expression, again suggesting subtype-specific expression patterns [ 36 ]. In vitro studies of Gli-1 have shown high levels of expression in SUM145 cells, which are basal type B as well as triple negative, yet it was not increased in other triple negative and basal-like breast cancer lines, including MDA-MB-231.…”

“…Thus, suggesting that other factors contribute to high Gli-1 expression in these cells [ 32 ]. On the other hand Gli-1 expression was lower in the ER-positive breast cancer cell lines T47D and MCF7 [ 36 ]. Studies of Gli-1 in vivo report increased expression in four out of five paired normal and tumor clinical samples, which was not statistically significant, which could be due to small sample size [ 45 ].…”

“…Ptch- 1, on the other hand, was reported to regulate cell cycle progression and high expression of Ptch-1 has been associated with metastasis in many human cancers [ 53 ]. It was observed that expression of Ptch-1 was significantly decreased in breast cancer compared to mammary hyperplasia [ 36 ]. A study suggested that the mRNA of Ptch-1 and Gli-1 in core needle biopsy would provide a useful tool for surgeons and patients for the selection of treatment options in the clinical management of breast cancer [ 34 ].…”

Pathways to Breast Cancer Recurrence

“…In one such study [126], it was observed that Gli1 expression correlated well with basal breast cancer subtype, and the patients with high nuclear expression of Gli1 had significantly reduced survival time. In another study that focused on triple negative breast cancers [127], it was observed that Smoothened and Gli1 were significantly upregulated in triple negative breast cancers, as compared to the other breast cancer subtypes. The individual members of hedgehog signaling, Shh, Gli1, and Smoothened, were found to correlate with increased metastasis and tumor grade while, at the same time, Gli1 expression was inversely associated with ER.…”