Targeting cell fusion as a novel strategy to tackle JQ1 resistance in triple negative breast cancer

Triple negative breast cancer (TNBC) remains an aggressive disease due to the lack of targeted therapies and low rate of response to chemotherapy that is currently the main treatment modality. Compared to other types of breast cancer, TNBC tumor consists of more immune cells in tumor mass. Recently inhibitors of bromodomain (BRD) proteins showed very promising results in treatment of cancer including TNBC. For example, JQ1 as a specific inhibitor of BRD4 blocks the growth of TNBC cells. However, JQ1 developed resistance in TNBC. In addition, only tumor cells were tested for JQ1 resistance, raising a concern of real recapitulation of the disease in this model. Therefore, to fully exploit the therapeutic benefit of JQ1, it is necessary to further explore the mechanisms of JQ1-induced resistance in the context of interactions between TNBC cells and immune cells. In our preliminary studies, we found that JQ1 treatment increased cell fusion between TNBC cells and one type of immune cells named monocytes. This process was likely mediated by inhibiting a mediator protein in cell fusion named Major Facilitator Superfamily Domain Containing 2 (MFSD2). Interestingly the fusion cells resemble breast cancer stem cells (BCSCs), the seed of breast cancer and critical to chemoresistance in TNBC. These findings led us hypothesize that targeting MFSD2-mediated cell fusion may be a novel strategy to prevent JQ1- mediated drug resistance in TNBC. To test our hypothesis, we have designed the following three specific aims. In Aim 1, we will examine whether JQ1 promotes cell fusion through inhibition of MFSD2 in monocytes. In Aim 2, we will examine whether MFSD2 mediates JQ1-induced phenotypical changes of BCSCs in vitro and in vivo. In Aim 3, we will examine whether JQ1 promotes cell fusion through BRD4-dependent and BRD4-independent manners by large scale sequencing techniques including CHIP-Seq and RNA-Seq. Successful completion of the project will lead to future identification of specific MFSD2 activators as drug candidates to prevent JQ1 resistance in TNBC. In addition, the proposal will be a great vehicle for training undergraduate students at Benedict College in cancer research using bioinformatics and other techniques in molecular biology.