Identification and Characterization of Epigenetic Regulators of Breast Cancer Metastasis to the Brain

Abstract

Breast cancer is the second leading cause of cancer-related deaths in the US, primarily because breast cancer cells metastasize multiple vital organs, including the brain. Brain metastases, refractory to chemotherapy, occur in approximately 15-35% of metastatic breast cancer cases. Current clinical management of brain metastases is limited to radiation therapy and surgical resection, and the median survival time for patients is very short. Therefore, a better therapeutic strategy against the disease is urgently needed. Emerging evidence suggests that metastasis's key steps are controlled by reversible epigenetic mechanisms, which could be targeted to prevent and treat the condition. Using a systematic in vivo shRNA screening approach, which targets around 100 actionable epigenetic regulators, we have identified several potential drivers and suppressors of breast cancer brain metastasis. Interestingly, one of the candidate regulators, N-acetyltransferase 10 (NAT10), plays a role in catalyzing acetylation on specific RNA and protein substrates, while its regulatory mechanisms in breast cancer remain unclear. We found that knockdown of NAT10 suppresses breast cancer cell proliferation and migration in vitro and brain metastasis in vivo. We are leveraging transcriptomic and proteomic analyses to uncover key biological pathways regulated by NAT10. Here, we have demonstrated that this screening strategy is potent and can be applied to identify critical epigenetic regulators in other cancer types or metastatic organs. Our results allowed us to uncover the metastatic organotropism of the epigenes and develop a novel therapeutic regimen against metastatic diseases.