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

SIMPLE SUMMARY: Syndecans (SDCs; SDC1 to 4) are integral cell surface proteoglycans that are expressed normally on various types of mammalian tissues. In cancer, SDCs’ expression is dysregulated, impacting the onset and progression of cancer by modulating pivotal signaling pathways involved in biological and molecular functions. In this review, we highlight the key roles of SDCs in breast cancer pathogenesis, addressing the prognostic value and the critical molecular regulators of SDC expression, as well as different SDC-centered therapeutic perspectives. 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.