Abstract LB-020: The replication factor MCM10 maintains breast cancer stem-like cells that constitutively experience c-Myc-driven replication stress

Abstract

Abstract Cancer stem-like cells (CSCs) are thought to be responsible for recurrence of tumors and poor prognosis due to their higher tumor-initiating capacity and resistance against chemotherapeutic agents, although the underlying mechanisms remain unclear. Here, we uncover a critical role of the replication factor mini-chromosome maintenance protein 10 (MCM10) in enabling breast cancer-derived CSCs to deal with constitutively accumulating DNA replication stress. Transcriptomic analysis of patient-derived breast cancer cells revealed that c-Myc downstream target genes and replication stress response genes were highly upregulated in CSC-enriched spheroid cells. Upregulated c-Myc enhanced the transcriptional activity especially at nucleoli, leading to DNA replication stress caused by collision of transcription and replication machineries. MCM10, one of the most upregulated factors in CSCs, showed important roles for enabling cells to survive under such condition through activating dormant origins. MCM10 depletion decreased tumorigenesis, tumor sphere-forming capacity, expression levels of stemness markers, and tumor-initiating capacity, suggesting that elevated MCM10 levels are vital for CSC survival and proliferation. On the other hand, overexpression of MCM10 helped cells to proliferate in medium containing hydroxyurea (HU), a chemotherapeutic agent that induces replication stress. We therefore conclude MCM10 plays critical roles for cancer cell proliferation under DNA replication stress, which is more pronounced in CSCs with upregulated c-Myc activity and in cells treated with chemotherapeutic agents, and propose to target MCM10 for therapy of both CSCs and other cancer cells. Citation Format: Noriko Gotoh. The replication factor MCM10 maintains breast cancer stem-like cells that constitutively experience c-Myc-driven replication stress [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-020.