Dormancy is an unmet clinical need in breast cancer. Although five-year survival rates are high, one out of five breast cancer patients will suffer relapse. Breast cancer cells can spread from primary tumours early during disease progression, even before diagnosis. These disseminated tumour cells (DTCs) can enter a dormant state that allows their survival during treatment. These dormant cells are likely to be the source of cancer recurrence.
MYC is a well-known oncogene aberrantly regulated in many cancers, including breast cancer. The gene is involved in stemness, tumorigenesis and diapause. We hypothesise that MYC is also a master regulator of dormancy.
Inducible genetic suppression of MYC results in a dormant phenotype in human breast tumour cells in vitro. In mice, loss of MYC greatly reduces the extent of metastasis following tumour resection. The DTCs in lungs, livers and bone are maintained as small clusters, while untreated mice display many and large metastases. DTCs can be sustained in this dormant-like state for more than 32 days after tumour removal. Importantly, when MYC levels are restored, the DTCs exit the dormant state, and overt metastasis ensues.
Transcriptomic analysis of dormant cancer cells revealed downregulation of cell cycle and biosynthesis; and the upregulation of survival mechanisms. Future analysis will elucidate potential dormancy-specific genes from the generated dormancy signature to target clinically and will investigate whether the signature can be used to predict relapse-free survival.
Pharmacological inhibition of MYC by the BET protein inhibitor I-BET151 induced dormancy in vitro. Exposure to the compound also resulted in a significant reduction of metastasis in lungs, livers and spines of treated mice compared to control mice. Ultimately, treatment with I-BET151 combined with a therapy targeting a dormancy-specific gene identified from the gene expression data could lead to the induction of dormancy and potentially to the eradication of dormant cancer cells, permanently preventing relapse.