Attracted by mutated cells in a highly fusogenic environment might themselves become partners in cell–cell fusion events, which might lead to genetic reprogramming and the generation of cancer stem cells. CSCs are a minor subpopulation of cancerous cells that are defined by their ability to self-renew and differentiate to give rise to tumors and the heterogeneous cells within the tumor. The objective of the present study was to examine whether the fusion of TAMs and Dinaciclib breast cancer cells results in the genetic reprogramming and generation of CD44+ CD242/low breast cancer stem cells, which may contribute to metastasis and relapse. Cancer is a heavy burden on public health, and one of the leading causes of disease-associated death. Though great progress has been made in cancer prevention and treatment, its carcinogenesis is still ambiguous. Metastasis largely underlies the difficulty in successfully treating cancer. Thus, clarifying how metastasis occurs could be crucial for the identification of novel therapeutic targets to improve cancer treatment. EMT aids cell motility, the key prerequisite for tumor cell dissemination. Recent reports have shown that the induction of EMT in immortalized human breast epithelial cells is associated with the acquisition of BCSCs-associated properties, as demonstrated by the increased expression of CD44+ /CD242/low cells as well as the ability to form mammosphere colonies in culture. Taken together, the gain of motility and the acquisition of CSCs-associated properties by cancer cells could pave the way to metastasis. The idea that cell fusion contributes to cancer progression was introduced almost 100 years ago with a proposal that malignancy is a consequence of hybridization between leukocytes and somatic cells, and Melanoma 6 macrophage hybrids with enhanced metastatic potential. Years later, this idea was expanded to encompass that cell fusion promotes the phenotypic and genotypic diversity of tumors and that the fusion of tumor cells with leukocytes results in metastatic cells. Cell fusion is a part of normal development and tissue homeostasis.In humans and results in terminally differentiated multinuclear cells incapable of proliferation, such as syncytiotrophoblasts, myoblasts, and osteoclasts. Intriguingly, as a fusion partner, tumor cells appear to violate the strict rules of cell fusion. Hybridization between TAMs and breast cancer cells as a mechanism for breast cancer metastasis presents the cancer cell in a different light: such hybrids, with features of both parental lineages, can transfer to blood circulation freely, as illustrated in Figure 6. Although their genetic complement would be random at the very beginning, common traits would emerge based on Darwin’s theory of evolution: survival of the fittest, which could be due to the survival benefits derived from some gene-expression patterns or to the nature of hybridization that controls gene expression in hybrid genomes of different embryonic lineages by unknown mechanisms. The onset of metastasis is still unclear; however, breast cancer metastasis seems to be at least partially due to the acquisition of myeloid-type traits. In breast cancer, the abundance of infiltrating macrophages has been correlated with poor prognosis, and genes associated with macrophage infiltration are part of a molecular signature that heralds negative prognosis in nodenegative, tamoxifen-treated breast carcinomas. Though the expression of M2 macrophage-specific antigen CD163 varied significantly in primary breast cancer, its prevalence has a prognostic impact on both relapse-free survival and overall survival, which could be explained by fusion between macrophages and cancer cells.