Triple negative breast cancers (TNBCs), i.e., 10-15% of diagnosed breast cancers, have a triple negative (Her/2-, ER- and PR-) phenotype and are the most aggressive subtype of breast cancer. TNBCs have a worst prognosis because of the high probability of metastasis and limited treatment options. The role of chemokine – chemokine receptor CXCL12-CXCR4 signaling axis in the progression and metastatic spread of breast cancer is well established. Especially, CXCL12 promotes cell migration, an essential step in cancer metastasis. Over the past decades, multiple targeted therapeutic strategies aiming to the block the CXCR4 signaling have been assessed. However, their clinical uses remain challenging because of side-effects due to the abundant CXCR4 expression on numerous cell types and its involvement in normal physiological processes. Therefore, new therapeutic approaches without side-effects are required for improving treatments of metastatic breast cancers. The present PhD thesis provides evidence in support of an alternative approach targeting the CXCL12-CXCR4 signaling through heterophilic interactions with chemokine CXCL4 to neutralize CXCL12-CXCR4 driven tumor migration. We first investigated whether CXCL4 heterodimerized with CXCL12 and the biological relevance of CXCL4-CXCL12 heterodimers in breast cancer migration. Our data show that CXCL4 and CXCL12 formed heterodimers via the interactions of the first -strands from CXCL4 and CXCL12 monomers. Interestingly, treatments with combinations of CXCL12 with increasing concentration of CXCL4 dose-dependently reduced the migration of CXCR4-expressing triple negative breast cancer cells. The different oligomeric species of chemokines present in equilibria and, in particular, the competition between the homodimers and heterodimers likely hampers assessments of the biological relevance of chemokine heterodimers. Therefore, next, we used a novel disulfide-trapping method to produce a non-dissociating CXCL4-CXCL12 heterodimer designed with inter-molecular disulfide bond that prevents two monomeric units from dissociation. We, then, assessed the biological function of the obligate CXCL4-CXCL12 heterodimers in breast cancer migration. The obligate CXCL4-CXCL12 heterodimers were shown to prevent breast cancer migration. Particularly, through competition with the wildtype CXCL12, the obligate CXCL4-CXCL12 heterodimers reduced CXCL12-driven migration. We also demonstrated that the obligate CXCL4-CXCL12 heterodimers are biologically active and promote the release of intracellular calcium, a key evidence of G-protein activation through the CXCR4 receptor. Taken together, our data indicate that the obligate CXCL4-CXCL12 heterodimer inhibits breast cancer cell migration, at least in part, through the competition for the CXCR4 receptor. Lastly, these data are discussed, and future research outlined to exploit chemokine heterodimerization as a potential target in breast cancer progression. We also highlight the potential of chemokine antagonism by peptides mimicking the heterophilic interactions as a valid therapeutic approach to prevent breast cancer progression.