Revisiting the Syndecans: Master Signaling Regulators with Prognostic and Targetable Therapeutic Values in Breast Carcinoma

Abstract

Syndecans (SDC1 to 4), a family of cell surface heparan sulfate proteoglycans, are frequently expressed in mammalian tissues. SDCs are aberrantly expressed either on tumor or stromal cells, influencing cancer initiation and progression through their pleiotropic role in different signaling pathways relevant to proliferation, cell-matrix adhesion, migration, invasion, metastasis, cancer stemness, and angiogenesis. In this review, we discuss the key roles of SDCs in the pathogenesis of breast cancer, the most common malignancy in females worldwide, focusing on the prognostic significance and molecular regulators of SDC expression and localization in either breast tumor tissue or its microenvironmental cells and the SDC-dependent epithelial-mesenchymal transition program. This review also highlights the molecular mechanisms underlying the roles of SDCs in regulating breast cancer cell behavior via modulation of nuclear hormone receptor signaling, microRNA expression, and exosome biogenesis and functions, as well as summarizing the potential of SDCs as promising candidate targets for therapeutic strategies against breast cancer.

Keywords: breast cancer; epithelial–mesenchymal transition; exosomes; microRNAs; nuclear hormone receptors; syndecans; therapeutic perspectives; tumor microenvironment.

Figure 1

Estrogen receptor (ER) signaling pathway. Two signaling pathways are known to mediate ER signaling, including genomic (ligand-dependent and -independent) and non-genomic pathways. In ligand-dependent genomic pathways, estradiol (E2) can bind to ER to induce transcription of estrogen response element (ERE) genes. In ligand-independent genomic pathways, phosphorylation of ER is mediated by EGF/EGFR or IGF/IGFR-induced PI3K/AKT and MAPK activation. On the other hand, the non-genomic pathway is regulated by membrane-bound ER or G-protein coupled ER (GPER), whereby binding to E2 leads to activation of PI3K/AKT and MAPK signaling.

Figure 2

Schematic diagram showing the possible crosstalk between syndecans (SDCs) and estrogen receptors (ER) in breast cancer cells. In ERα-negative cells, (A) silencing of ESR2 in MDA-MB-231 breast cancer cells induces the expression of SDC1, 2, and 4, and (B) estradiol (E2)-induced SDC2 expression depends on IGFR signaling crosstalk. In ERα-positive cells, (C) ERα activation by E2 in IKK-dependent mechanisms enhances ERα stability and transcriptional activity, leading to SDC1 repression, (D) EGFR mediates E2 inhibitory action on SDC4 expression and E2-induced SDC2 expression, (E) IGFR inhibits aggressiveness of ERα-dependent MCF-7 by sustaining the expression of SDC4, and (F) IGFR colocalizes with SDC4, and that IGFR blocking results in SDC4 endocytosis and aggressiveness phenotype.

Figure 3

Bidirectional relations between SDCs (SDC1 and 4) and miRNAs in breast cancer. SDC1 expression can be directly or indirectly targeted by miR-10b, miR-122-5p, miR-145, and miR-335-5p, whereas SDC4 is directly targeted by miR-140-3p. On the other hand, downregulation of SDC1 results in reduced miR-10b expression. The interplay between SDCs and miRNAs ultimately affects breast cancer cell behavior (e.g., cell proliferation, adhesion, migration, and invasion).

Figure 4

Summary diagram for different therapeutic approaches that can be used for syndecans (SDCs) targeting breast cancer. This includes monoclonal anti-SDC1 antibodies, immunoconjugates linked to cytotoxic drugs, or radiolabeled antibodies (immunoradiotherapy). Further therapeutic perspectives include the application of different types of pharmaceutical agents or inhibitors, such as peptide inhibitors (to impede their interactions with integrins or RTKs), small molecule inhibitors, and HS mimetics (or their nanoformulations, e.g., nanoheparin), or inhibitors for exosomal packing (e.g., SyntOFF inhibitors targeting the PDZ2 domain of syntenin). For further details, please refer to the text.