Project Summary/Abstract Approximately 90% of breast cancer-related deaths are caused by local invasion and distant metastasis of tumor cells. While invasive breast cancer incidence rates have been stabilized in white women in the recent decade, a steady increase in the incidence rates by 0.3% per year has been observed in black women. Meanwhile, the survival rates for invasive breast cancer have increased for both populations over time. However, they remain 10% lower for black women. Although the reasons for these disparities are multifactorial, differences in molecular mechanisms and signaling pathways driving the progression of the disease might account at least in part for the survival disparity. Triple negative breast cancer is more common in black women and was shown to exhibit extensive genomic heterogeneity and resistance to drug. In this study, we assess cancer cell fusion as a mechanism driving tumor heterogeneity and metastasis and a potential basis for the disproportion in breast cancer heterogeneity between white and black women. Different hypotheses have been put forward as to how metastasis develops. However, exactly how each of the mechanisms proposed so far is accomplished is yet to be established. Studies have suggested that metastatic cells result from the fusion of primary tumor cells and cells of hematopoietic lineage. Some reports including ours showed that fusion enables rapid diversification and subsequent intra-tumor heterogeneity supportive of metastasis. We observed that breast cancer cell fusion happens in vivo and contributes to metastasis. We also showed that fusion between non metastatic breast cancer cells and mesenchymal/multipotent stem/stromal cells (MSCs) was enhanced with hypoxia by a mechanism involving apoptosis and dependent of the phosphatidyl-serine (PtdSer) receptor BAI1. BAI1 and apoptotic cells were recently identified as new promoters of myoblast fusion by means of signaling through ELMO/Dock180/Rac1 pathway. The ELMO/Dock180/Rac1 pathway is activated in breast cancer. We therefore hypothesize that hypoxia stress-induced apoptosis in primary tumors stimulates fusion between tumor cells and cells of the tumor microenvironment by a mechanism involving BAI1 activation and signals through ELMO/Dock180/Rac1 pathway. Our objective is to investigate the role of BAI1/ELMO/Dock180/Rac1 pathway in the mechanism of fusion of breast tumor cells isolated from both white and black women with MSCs in vitro. We will also determine the function of BAI1 in breast cancer metastasis in vivo by analyzing the ability of breast specific Bai1 knockout mice in the FVB/N-Tg(MMTVPyVT)634Mul/J background to develop breast cancer metastasis. The completion of this study would contribute to delineating the mechanisms of cancer cell fusion, the role of cancer cell fusion in the development of molecular diversity in breast tumors, and potentially the mechanisms of metastases. This study might provide new strategies to developing a different class of drugs for breast cancer treatment and/or prevention of metastatic spread. This would contribute to the reduction in breast cancer disparities in our communities.

Narrative This study proposes a novel mechanism of how cancer cells fuse with other cells, an event that could explain how cancer cells move from their original location to other sites in the body and form new tumors or metastases. The results from this study might provide new insights for the development of drugs for cancer treatment and/or preventing the spread of cancer cells.