Abstract P2-02-08: Chromosome 8q gain-related transcription factor MYBL1 is a critical regulator in triple-negative breast cancer

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Abstract Chromosome arm-level aneuploidies (CAAs) are a common consequence of genomic instability during the evolution of solid tumor and often associated with metastasis and therapy resistance. In breast cancer, chromosome arms 1q and 8q are the frequent amplified regions for CAAs. This study aims to investigate whether critical genes amplified in genomic regions with CAAs contribute to the pathophysiology in triple-negative breast cancer (TNBC). We established multiple long-term culturable TNBC patient-derived cells (PDCs) using spheroid culture technique, which is favorable for the enrichment of cell population with cancer stemness. We performed a genome-wide chromatin immunoprecipitation study for histone H3K27ac and super-enhancer analysis in these TNBC PDCs and cell lines. Super-enhancer analysis revealed that 8q is a substantial chromosomal region with a high density of super-enhancers. Among genes in the vicinity of 8q super-enhancers, we identified that MYB proto-oncogene like 1 (MYBL1) is a transcription factor with high abundance in TNBC PDCs as well as in basal-like BT549 cells. In TCGA breast cancer database, 8q gain is a common genomic feature in MYBL1 gene-amplified breast cancer tissues and MYBL1 expression is substantially correlated with 8q-related genes and proliferation-related genes like MKI67 and BUB1. In TNBC PDCs and cell lines, we showed that MYBL1-specific siRNAs significantly repressed TNBC cell proliferation and migration. RNA sequencing analysis in TNBC cells revealed that MYBL1 silencing substantially downregulated genes involved in the transcription machinery such as nuclear envelope, chromatin dynamics, and DNA replication. In immunohistochemical analysis of clinical TNBC tissues from a Japanese cohort, we showed that a positive MYBL1 immunoreactivity (IR) was significantly associated with shorter disease-free survival (DFS). Among candidate MYBL1 targets, we demonstrated that NCAPH, a subunit of condensin I complex, was a prognostic factor for patients with TNBC based on the immunohistochemistry of clinical TNBC tissues. Notably, patients with double IR positivity for MYBL1 and NCAPH showed shorter DFS than those with MYBL1 or NCAPH positivity alone. MYBL1 has been characterized as an essential transcriptional regulator in male meiosis and in female mammary gland development. Our findings indicate that MYBL1 plays an essential role in the pathophysiology for advanced breast cancers such as TNBC, and MYBL1 and its downstream genes can be potential diagnostic and therapeutic targets for the disease. Citation Format: Akihiro Fujimoto, Kazuhiro Ikeda, Keiichi Kinowaki, Hidetaka Kawabata, Akihiko Osaki, Satoshi Inoue, Kuniko Horie. Chromosome 8q gain-related transcription factor MYBL1 is a critical regulator in triple-negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-02-08.

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