Abstract A010: MYC as a master regulator of dormancy in triple negative breast cancer

Abstract

Abstract Dormancy is a major clinical problem in breast cancer. Although the five-year survival rate is high, 15% of the patients will relapse. Cancer cells that disseminate from the tumor (DTCs) can enter a dormant state that allows survival in the face of standard-of-care therapies. These DTCs are the source of cancer recurrence. Currently little 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 tumors, the loss of MYC activity following primary tumor 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 for at least 32 days after primary tumor 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 actively growing metastatic cells to generate a MYC-driven dormancy signature that will elucidate potential dormancy genes to target therapeutically in the clinic. To complement our genetic studies, we are investigating pharmacological suppression of MYC activity. The bromodomain inhibitor I-BET151 reduces MYC protein levels and induces dormancy in our in vitro assay. Mice treated with I-BET151 after primary tumor 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 that 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. Citation Format: Charlotte Roelofs, Kellie A. Mouchemore, Anannya Chakrabarti, Richard P. Redvers, Robin L. Anderson. MYC as a master regulator of dormancy in triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A010.