Interactions between hedgehog signaling pathway and the complex tumor microenvironment in breast cancer: current knowledge and therapeutic promises

Abstract

Breast cancer ranks as one of the most common malignancies among women, with its prognosis and therapeutic efficacy heavily influenced by factors associated with the tumor cell biology, particularly the tumor microenvironment (TME). The diverse elements of the TME are engaged in dynamic bidirectional signaling interactions with various pathways, which together dictate the growth, invasiveness, and metastatic potential of breast cancer. The Hedgehog (Hh) signaling pathway, first identified in Drosophila, has been established as playing a critical role in human development and disease. Notably, the dysregulation of the Hh pathway is recognized as a major driver in the initiation, progression, and metastasis of breast cancer. Consequently, elucidating the mechanisms by which the Hh pathway interacts with the distinct components of the breast cancer TME is essential for comprehensively evaluating the link between Hh pathway activation and breast cancer risk. This understanding is also imperative for devising novel targeted therapeutic strategies and preventive measures against breast cancer. In this review, we delineate the current understanding of the impact of Hh pathway perturbations on the breast cancer TME, including the intricate and complex network of intersecting signaling cascades. Additionally, we focus on the therapeutic promise and clinical challenges of Hh pathway inhibitors that target the TME, providing insights into their potential clinical utility and the obstacles that must be overcome to harness their full therapeutic potential.

Keywords: Breast cancer; Hedgehog signaling pathway; Therapeutics; Tumor microenvironment.

Fig. 1

Activation and regulation of Hh pathway in vertebrates. The canonical Hh signaling pathway is initiated by the binding of Hh ligands to the transmembrane protein Ptch, which inhibits the Ptch-dependent suppression of Smoothened SMO, leading to the activation of the Gli signaling pathway. Left panel: In the presence of Hh ligands, the engagement of these ligands—IHh, Shh, or DHh—with the Ptch receptor results in the alleviation of Ptch’s inhibitory effect on Smo. Subsequently, the activated Smo conveys the Hh activation signal into the cytoplasm. Ultimately, the Suppressor of Fused (Sufu) releases Gli proteins from the cytoplasm, enabling their translocation to the nucleus, where they initiate the transcription and expression of their target genes, including Gli1, Gli2, and Gli3. Right panel: In the absence of Hh ligands, Ptch liberates proteins that inhibit Smo activity, thereby preventing Smo activation and shutting down the Hh signaling pathway

Fig. 2

Complex mechanisms of Hh pathway remodelling of TME in breast cancer. Hh signaling pathway plays a key role in the breast cancer microenvironment, affecting the function of tumor cells and immune cells. Treg cells often secrete inhibitory factors to hinder immune response. Hh signals regulate Treg/Th17 axis through metabolic remodeling, limit CD8 cell infiltration, and promote immune escape. TAMs polarize M2 under Hh signal, reduce CXCL9/10 production, inhibit CD8 T cell infiltration, and inhibit its function through PD-L1 expression. Hh signaling also reprograms CAFs to increase fibrocollagen and FGF5 expression, supporting tumor stem cell resistance. CCL2, CCL5 and IGF-1 secreted by CAFs activate the Hh signal in cancer cells, forming a vicious cycle that promotes tumor growth and drug resistance. CA-MSCs accelerate breast cancer bone metastasis by regulating immune response and promoting osteoblast differentiation. In addition, vascular endothelial growth factor (VEGF), pro-angiogenesis secretory molecules CYR61, IL-6, etc. all work synergically with Hh signaling pathway to strengthen the malignant behavior of breast tumor cells, promote the proliferation of cancer cells and enhance tumor drug resistance. Hypoxia and acidic tumor microenvironment are important factors that promote tumor invasion and metastasis and lead to poor prognosis of breast cancer patients

Fig. 3

Communication between the Hh signalling pathway and other pathways in breast cancer TME. The regulatory role of Hh signaling pathway in breast cancer is complex, involving a variety of signaling pathways, including Wnt/TGF-β/Notch/RAS/MAPK/NF-κβ/PI3K pathways. They have direct effects on target genes or activation of transcription factors through various mechanisms to affect cell behavior. For example, in the crosstalk with the North pathway, Hh promotes tumor cell proliferation and inhibits apoptosis by regulating its key target gene jagged2. In addition, Shh does not require γ-secretase to cut Notch receptor, and can directly act on Hes1 to promote tumor cell development. In endocrine-resistant breast cancer, activation of PI3K/AKT pathway receptors such as EGFR and IGF1-R stabilizes SMO and Gli1 proteins by affecting GSK3β-mediated phosphorylation and proteasome degradation. In the NF-κB pathway, various stimuli (such as TNF-α) activate the IκB kinase (IKK) complex and phosphorylate the IκB inhibitory protein, leading to ubiquitination and subsequent degradation of the IκB protein, thereby releasing proteins of the NF-κB family (such as P65, P50, etc.), mediating the up-regulation of Gli1 and SHh expression. In TGF-β pathway, the formation of complexes between phosphorylated Smad2/3 and Smad4 can effectively induce Gli1, Gli2 and their target gene PTH-rP (osteoclast formation regulator), and promote osseolytic metastasis of breast cancer. The RAS pathway phosphorylates and activates MEK (MAPKK) and ERK (MAPK) in sequence through integrin conduction and downstream effector Raf activation in the absence of Hh ligand, and finally the activated ERK enters the nucleus to activate Hh signaling pathway ligand GLI. In the Wnt pathway, the key molecule β-catenin enhances the transcriptional activity of GLI and participates in the Hh signaling pathway. In the absence of Hh signaling, the transcription factor Gli3 (Gli3R) interacts with the carboxy-terminal domain of β-catenin, blocking classical Wnt signaling. This mechanism may provide reference for the development of cancer treatment drugs

Fig. 4

Hh signalling pathway inhibitors targeting TME in breast cancer. Utilizing a multitude of promising approaches to inhibit the Hh signaling pathway may offer significant contributions to therapeutic strategies for breast cancer treatment. Current inhibitors targeting Hh signaling include small molecule inhibitors and natural compounds. These small molecule inhibitors are broadly categorized into: SMO inhibitors (e.g., Cyclopamine, Vismodegib, Sonidegib), HHh inhibitors (e.g., 5E1, RU-SKI 43), and GLI inhibitors (e.g., GANT61, Arsenic trioxide [ATO], HPI-1, JK184). In addition, several naturally occurring compounds have been identified as inhibitors of the Hh signaling pathway, such as Huaier aqueous extract, Genistein from soy and other plants, Cananginones from Annona, Pterostilbene from blueberries and grapes, Solasodin from Solanum incanum L, Sinomenine from Sinomenium acutum, Curcumin from Curcuma longa L, Physalin A from Physalis alkekengi, Wogonoside from Scutellaria baicalensis Georgi, Nitidine Chloride from Zanthoxylum nitidum (Roxb.) DC, Norcantharidin from Mylabris phalerata Pallas, and Cordycepin from Cordyceps militaris