Lymphangiogenesis in Breast Cancer: From Molecular Mechanisms to Clinical Implications

ABSTRACT Despite the recent advances in treatment, breast cancer (BCa) remains a leading cause of cancer‐related mortality worldwide, and metastasis accounts for the most significant number of BCa deaths. Lymphangiogenesis, the process by which new lymphatic vessels develop from pre‐existing ones, is a major driver of BCa metastasis. High lymphatic vessel density is linked to lymph node metastasis and poor prognosis in BCa. Vascular endothelial growth factor receptor 3 (VEGFR3) and its ligands vascular endothelial growth factor C (VEGF‐C) and VEGF‐D have been described as key players in BCa‐induced lymphangiogenesis. However, the molecular mechanisms associated with lymphangiogenesis in BCa are not fully understood. In this review, we discuss how the local breast tumor microenvironment modulates the process of lymphangiogenesis to facilitate disease progression and provide a mechanistic insight into the complex formation of lymphatic vessels in BCa, highlighting the role of the VEGF‐C, D/VEGFR3 signaling axis, along with other molecular players. Additionally, the review discusses the versatile therapeutic potential targeting lymphangiogenesis in BCa and challenges that need to be overcome in the future. A complete understanding of lymphangiogenesis in BCa will open up new possibilities for targeted therapeutics that can potentially improve outcomes for BCa patients and the efficacy of current treatments.