Role of Hedgehog Signaling in Breast Cancer: Pathogenesis and Therapeutics

Abstract

Breast cancer (BC) is the leading cause of cancer-related mortality in women, only followed by lung cancer. Given the importance of BC in public health, it is essential to identify biomarkers to predict prognosis, predetermine drug resistance and provide treatment guidelines that include personalized targeted therapies. The Hedgehog (Hh) signaling pathway plays an essential role in embryonic development, tissue regeneration, and stem cell renewal. Several lines of evidence endorse the important role of canonical and non-canonical Hh signaling in BC. In this comprehensive review we discuss the role of Hh signaling in breast development and homeostasis and its contribution to tumorigenesis and progression of different subtypes of BC. We also examine the efficacy of agents targeting different components of the Hh pathway both in preclinical models and in clinical trials. The contribution of the Hh pathway in BC tumorigenesis and progression, its prognostic role, and its value as a therapeutic target vary according to the molecular, clinical, and histopathological characteristics of the BC patients. The evidence presented here highlights the relevance of the Hh signaling in BC, and suggest that this pathway is key for BC progression and metastasis.

Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments

“…Liu et al found that genetic ablation of SMO in stromal fibrosis could disrupt the paracrine SHH signaling with acinar-ductal metaplasia under a Kras G12D mouse model [90]. 4 -bis(2-pyridinylmethyl)-1,4-benzenedicarboxamide (MDB5) to inhibit pancreatic cancer [80]. Using a mouse model, Olive et al reported that SMO inhibitor enhances the vasculature within the tumor and facilitates the delivery of chemotherapy agents to pancreatic cancer [92].…”

“…[114][115][116][117][118][119]. During embryonic development, the canonical SHH signaling pathway is inhibited in breast tissues [4,111], and SHH gene expression is affected temporally and spatially via genetic and epigenetic mechanisms [4,111]. In a mouse study, early mammary bud formation was found to require active repression of GLI1 by GLI3R [4].…”

“…During embryonic development, the canonical SHH signaling pathway is inhibited in breast tissues [4,111], and SHH gene expression is affected temporally and spatially via genetic and epigenetic mechanisms [4,111]. In a mouse study, early mammary bud formation was found to require active repression of GLI1 by GLI3R [4]. During puberty, ductal morphogenesis is affected by canonical and non-canonical SHH signaling, for which type I non-canonical SHH signaling plays an essential role [4,111].…”

“…In a mouse study, early mammary bud formation was found to require active repression of GLI1 by GLI3R [4]. During puberty, ductal morphogenesis is affected by canonical and non-canonical SHH signaling, for which type I non-canonical SHH signaling plays an essential role [4,111]. During puberty, the elongation of the terminal buds is affected via activation of cellular Src kinase (c-Src), estrogen receptor alpha (ERα), and extracellular signal-regulated kinase (ERK) cascades in mammary luminal epithelial cells [120][121][122].…”

“…Tumor microenvironment/stroma can affect tumor development and metastasis [4,5]. The tumor microenvironment/stroma includes endothelial cells, immune cells, adipocytes, and activated fibroblasts (the so-called "cancer-associated fibroblasts" (CAFs)) [6].…”