This resultant hybrid adopts the leukocyte’s natural ability to migrate throughout the body while continuing to grow in the uncontrolled manner of the original cancer. This model is also known as the “wolf in sheep’s clothing” model and explains how hybrids evade immune supervision. Additionally, periodically refreshing the genome with bone marrow-derived cells may contribute to telomeric maintenance, which is essential for the survival of tumor cells and may be a characteristic of CSCs. In a very recent article, Rappa G and colleagues reported that a spontaneous in vitro formation of heterotypic hybrids between human bone marrow-derived multipotent stromal cells and ASP1517 HIF inhibitor breast carcinoma cell lines exhibits a more aggressive behavior. Here, we used the U937 cell line as a substitute for primary human monocytes. Although the use of primary cells would allow stronger conclusions, the enrichment of primary human monocytes involves many ethical issues. We have demonstrated that the tumorigenicity and invasiveness of the fusion hybrids increased significantly in the weakly tumorigenic MCF-7 breast cancer cell line without estrogen implantation. However, the proliferative ability of the fused cells is weaker than their parental counterpart in vitro, which may be interpreted that the hybrids may undergo programmed cell death if reprogramming fails after fusion, as illustrated in Figure 6. The essence of cancer stem cells, which are in a quiescent state but can rapidly expand and differentiate in response to environmental cues, may be also possible. To our knowledge, this is the first report demonstrating direct experimental evidence that fusion of TAMs and breast cancer cells is a possible source of BCSCs, which may be the driver of metastasis and relapse. Based on this finding and previous reports, we graphically depicted the probable development of breast cancer in Figure 7. However, not all patients with breast cancer can educate monocytes to TAMs and form hybrids; therefore, the prognosis varies significantly even with early breast cancer. Thus, some patients may evade aggressive treatment for early disease after surgical intervention. In summary, TAMs play important role in breast cancer progression, and further studies are essential to elucidate how circulating monocytes are recruited to the tumor microenvironment and differentiate into TAMs. New strategies for tumor targeting and targeted chemotherapy could emerge from a better understanding of hybrid genetics and biology. Consequently, preventative treatment based on the suppression of tumor-cell fusion might be possible. RAS proteins constitute a family of signal-transducing GTPases involved in many basic cellular processes such as cell cycle progression and apoptosis. The inherent GTPase activity of RAS is controlled by guanine nucleotide exchange factors and GTPase-activating proteins, which promote the shuttling between the active and inactive states of the RAS proteins. Spatial and temporal activation of RAS proteins is tightly regulated, and aberrant RAS signaling can lead to congenital developmental disorders and oncogenic transformation. More than 15% of all human tumors contain activating mutations of the NRAS, KRAS, or HRAS homologs and in many other cases, overexpression or hyper-activation of the wild type protein has been described. Despite the high similarity among the RAS proteins, the aberrant expression of the different homologs is associated with particular types of human cancer. Additional evidence for differential functions of RAS homologs has been provided by genetically modified mouse models. While homozygous Nras and Hras single and double knock-out mice are viable and reproduce normally.