The Hedgehog signalling pathway in breast development, carcinogenesis and cancer therapy

Abstract

Despite the progress achieved in breast cancer screening and therapeutic innovations, the basal-like subtype of breast cancer (BLBC) still represents a particular clinical challenge. In order to make an impact on survival in this type of aggressive breast cancer, new targeted therapeutic agents are urgently needed. Aberrant activation of the Hedgehog (Hh) signalling pathway has been unambiguously tied to cancer development and progression in a variety of solid malignancies, and the recent approval of vismodegib, an orally bioavailable small-molecule inhibitor of Smoothened, validates Hh signalling as a valuable therapeutic target. A number of recent publications have highlighted a role for Hh signalling in breast cancer models and clinical specimens. Interestingly, Hh ligand overexpression is associated with the BLBC phenotype and a poor outcome in terms of metastasis and breast cancer-related death. In this review, we provide a comprehensive overview of the canonical Hh signalling pathway in mammals, highlight its roles in mammary gland development and breast carcinogenesis and discuss its potential therapeutic value in BLBC.

Selection of Personalized Patient Therapy through the Use of Knowledge-Based Computational Models That Identify Tumor-Driving Signal Transduction Pathways

“…We hypothesize that in ER-positive patients with an inactive ER pathway, other pathways such as Wnt or Hedgehog, associated with more aggressive behavior and worse outcome, may actually have been driving tumor growth (1,54,55). This is in agreement with the reported decline in SET index with advancing pathologic cancer stage, despite ER positivity, suggesting decreasing tumor dependency on an active ER pathway (53).…”

Breast cancer lung metastasis: Molecular biology and therapeutic implications

“…[78][79][80][81] Several recent studies have provided evidence that paracrine Hh signaling appears to be an important mechanism in breast cancer growth. 82,83 Moreover, Hh has been shown to regulate breast cancer cell migration. 84 We also found such paracrine signaling is associated with poor prognosis and the basal-like phenotype.…”

lncRNA Directs Cooperative Epigenetic Regulation Downstream of Chemokine Signals

“…GLI1/2-dependent target gene transcription has been shown to be involved in tumor cell growth and metastasis in solid tumors (Rubin and de Sauvage, 2006). However, GLI-target transcription might be activated in the absence of the hedgehog ligand Sonic Hedgehog (SHH), especially in triple-negative breast cancer (TNBC) (Hui et al, 2013), suggesting that other mechanisms/regulators may regulate the activity of the GLI transcription factor. The direct binding of lncRNAs to transcription factors (Geisler and Coller, 2013) led us to speculate that the association of transcription factor GLI with lncRNAs may function in regulating GLI-dependent transcriptional program essential for breast cancer progression and metastasis.…”