Master of Science
Triple-negative breast cancer (TNBC) is a heterogeneous group of tumours characterized by early metastases and poor prognosis. Discovering novel biomarkers and therapeutic targets is necessary to improve TNBC patient outcomes as resistance to chemotherapy, the main therapeutic approach for TNBC, is common. In my study, RHAMM promoted proliferation of TNBC MDA-MB-231 tumour cells. RHAMM expression increased sensitivity to doxorubicin (p=0.0002) and strongly increased sensitivity to the FDA-approved MEK1/2 inhibitor trametinib (p≤0.0001). Doxorubicin and trametinib selectively killed RHAMM+/+ MDA-MB-231 tumour cells grown as co-cultures with RHAMM-/- MDA-MB-231 tumour cells. RHAMM-loss or trametinib decreased phosphorylated ERK1/2 protein levels and promoted apoptosis through cell surface RHAMM/HA interactions. The combination of paclitaxel, a chemotherapeutic, and trametinib synergistically promoted apoptosis of the RHAMM+/+ MDA-MB-231 tumour cells. Therefore, RHAMM is a candidate novel biomarker in TNBC, and its expression can be exploited for targeted therapy, which has potential clinical utility for the management of TNBC.
Summary for Lay Audience
Triple-negative breast cancer (TNBC) is a type of breast cancer characterized by invasive tumour growth and poor patient survival outcomes. Development of resistance to current treatments, such as doxorubicin, is common. Therefore, identifying and developing effective therapies is required to improve patient outcomes. A protein called RHAMM has been reported to be highly expressed in breast cancer and my project was therefore focused on assessing if RHAMM expression in TNBC can help identify tumour cells that are more likely to die when exposed to different treatments, such as chemotherapy. In my study, the loss of RHAMM reduced TNBC cell proliferation, in part through the regulation of a protein called ERK1/2, which is highly expressed in TNBC. RHAMM expression increased the sensitivity of TNBC cells to the chemotherapeutic drug doxorubicin and trametinib, a drug that specifically targets MEK1/2, which is a highly active protein that promotes cancer progression. Doxorubicin and trametinib selectively killed RHAMM-expressing TNBC tumour cells that were grown with TNBC tumour cells that did not express RHAMM. RHAMM-loss or treatment with trametinib decreased the expression of activated ERK1/2 in the TNBC tumour cells and killed the tumour cells through the cell surface interaction of RHAMM and its binding partner HA. Furthermore, the combination of trametinib and a chemotherapy agent paclitaxel killed more RHAMM-expressing TNBC tumour cells than treatment with either drug alone. My results suggest that RHAMM expression in TNBC can be used as an indicator of sensitivity to treatment and that its expression and signalling can be used for targeted therapy, which has potential clinical significance for the management of TNBC.
Messam, Britney, "RHAMM as a biomarker and therapeutic target in triple-negative breast cancer" (2022). Electronic Thesis and Dissertation Repository. 8951.