Dormancy is a major clinical problem in breast cancer. Though the five-year survival rate is high, one in ten patients will relapse. Cancer cells that disseminated from the tumour (DTCs) can enter a dormant state that allows survival of standard-of-care therapies. These disseminated cells are the source of cancer recurrence. Currently not much is known about the molecular drivers that initiate dormancy.
MYC is a well-known oncogene that is aberrantly regulated in many cancers, including breast cancer. It is involved in proliferation, tumorigenesis, and diapause. We propose that MYC is also a master regulator of dormancy.
To investigate its role in dormancy we generated cell lines with regulatable levels of MYC expression. Using an in vitro dormancy assay, we have shown that reduced MYC levels induce dormancy in otherwise aggressive cell lines. In mice bearing human breast tumours, the loss of MYC activity following primary tumour removal greatly reduces the extent of metastasis. The DTCs in lungs, livers, spine, and femurs are maintained as small clusters with few cells, while control mice have many and large metastases. MYC reduction maintains the DTCs in this dormant-like state over 32 days post primary tumour removal. Importantly, when MYC levels are restored, the DTCs exit the dormant state, and overt metastasis ensues. Currently, we are comparing the transcriptomes of dormant DTCs to control cells to generate a MYC-driven dormancy signature to elucidate potential dormancy-genes to target therapeutically in the clinic.
To complement our genetic studies, we are investigating compounds that reduce MYC activity pharmacologically. BET inhibitor I-BET151 reduces MYC protein levels and induces dormancy in our in vitro assay. Mice treated with I-BET151 after primary tumour removal had significantly reduced levels of metastasis in lung, liver and spine, when compared to their non-treated counterparts. Testing of this compound in an immune-competent preclinical model is currently underway.
Our data imply MYC is an important regulator of dormancy in breast cancer. Our future experiments will elucidate dormancy genes as potential targets that could lead to life-saving therapies in the clinic.