Ramesh Butti, Totakura VS Kumar, Ramakrishna Nimma, Gopal C Kundu Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, Savitribai Phule Pune University, Pune, India Abstract: Breast cancer is one of the major causes of cancer-related deaths among women worldwide. Aberrant regulation of various growth factors, cytokines, and other proteins and their receptors in cancer cells drives the activation of various oncogenic signaling pathways that lead to cancer progression. Semaphorins are a class of proteins which are differentially expressed in various types of cancer including breast cancer. Earlier, these proteins were known to have a major function in the nerve cell adhesion, migration, and development of the central nervous system. However, their role in the regulation of several aspects of tumor progression has eventually emerged. There are over 30 genes encoding the semaphorins, which are divided into eight subclasses. It has been reported that some members of semaphorin classes are antiangiogenic and antimetastatic in nature, whereas others act as proangiogenic and prometastatic genes. Because of their differential expression and role in angiogenesis and metastasis, semaphorins emerged as one of the important prognostic factors for appraising breast cancer progression. Keywords: breast cancer, tumor microenvironment, semaphorins, plexins, neuropilins, cancer stem-like cells, prognostic factor, angiogenesis, metastasis, epithelial to mesenchymal transition, vascular endothelial growth factor