Abstract
Cell cycle control drives cancer progression and treatment response in high grade serous ovarian carcinoma (HGSOC). MYBL2 (encoding B-Myb), an oncogene with prognostic significance in several cancers, is highly expressed in most HGSOC cases; however, the clinical significance of B-Myb in this disease has not been well-characterized. B-Myb is associated with cell proliferation through formation of the MMB (Myb and MuvB core) protein complex required for transcription of mitotic genes. High B-Myb expression disrupts the formation of another transcriptional cell cycle regulatory complex involving the MuvB core, DREAM (DP, RB-like, E2F, and MuvB), in human cell lines. DREAM coordinates cell cycle dependent gene expression by repressing over 800 cell cycle genes in G0/G1. Here, we take a bioinformatics approach to further evaluate the effect of B-Myb expression on DREAM target genes in HGSOC and validate our cellular model with clinical specimens. We show that MYBL2 is highly expressed in HGSOC and correlates with expression of DREAM and MMB target genes in both The Cancer Genome Atlas (TCGA) as well as independent analyses of HGSOC primary tumors (N = 52). High B-Myb expression was also associated with poor overall survival in the TCGA cohort and analysis by a DREAM target gene expression signature yielded a negative impact on survival. Together, our data support the conclusion that high expression of MYBL2 is associated with deregulation of DREAM/MMB-mediated cell cycle gene expression programs in HGSOC and may serve as a prognostic factor independent of its cell cycle role. This provides rationale for further, larger scale studies aimed to determine the clinical predictive value of the B-Myb gene expression signature for treatment response as well as patient outcomes.
Highlights
High grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer [1]
Similar to invasive breast carcinoma, high expression of MYBL2 was significantly associated with poorer overall survival in The Cancer Genome Atlas (TCGA) cases (Figure 1B) [16]
MYBL2 was expressed at significantly higher levels in primary untreated ovarian carcinoma as compared with borderline ovarian surface epithelial-stromal tumor (Figure 1C) and ranked as the fourth most differentially upregulated gene among an independent data set (t-test 18.076, p = 5.99E-31, fold change 2.555, data not shown) [6, 16, 18]
Summary
High grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer [1]. Scientific understanding of this disease is a priority as ovarian cancer remains the most lethal of the gynecologic malignancies [2]. Better understanding of the factors that contribute to the pathogenesis and progression of HGSOC is required for improving the diagnostics and treatment of this disease. MYBL2 gene copy-number gain is present in 55% of HGSOC cases in both The Cancer Genome Atlas (TCGA) as well as data set; the prognostic importance of B-Myb in this disease has not been well-characterized [6]. Previous in vitro studies of cancer cell models found that high B-Myb expression deregulates the cell cycle through MMB formation and subsequent expression of genes required for mitosis, but leads to disruption of the repressor complex DREAM (DP, RB-like, E2F, and MuvB), a master regulator of the cell cycle dependent gene expression [7]
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