Dormancy is a clinical problem in breast cancer. Even though five-year survival rates are high, one out of ten of breast cancer patients will relapse. This relapse can happen years to decades after treatment and is a constant source of anxiety and fear for patients. Cancer cells that have disseminated from the tumour (DTCs) can enter a dormant state, which enables them to survive treatment. It is believed these cells are the source of cancer recurrence.
Myc is a well-known oncogene which is aberrantly regulated in many cancers, including breast cancer. The gene is involved in stemness, diapause, proliferation, and tumorigenesis. We hypothesise Myc is the master regulator of dormancy.
To investigate its role in dormancy we have generated multiple cell lines with inducible levels of Myc expression. We have reduced Myc levels and induced a dormant phenotype in otherwise aggressive cell lines. Vice versa, we have overexpressed Myc in naturally dormant cell lines which made them exit their dormant state. Ultimately, we will compare transcriptomics of dormant cells to proliferative cells to generate a dormancy gene signature and elucidate potential dormancy-specific genes to target in the clinic.
Our data have shown that a genetic reduction in Myc greatly reduces the extent of metastasis in a preclinical mouse model. The DTCs in lungs, livers, spine, and femurs are maintained in small clusters consisting of few cells, while the control mice have many and large metastases. We have sustained the DTCs in this dormant-like state for over 32 days post resection. Importantly, when levels of Myc are restored, the DTCs exit the dormant state, and overt metastasis ensues. This data imply Myc levels are important in the maintenance and exit of dormancy in DTCs.