# Mechanisms of B-Myb oncogenicity in ovarian cancer

> **NIH NIH F30** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $35,852

## Abstract

Project Summary-Abstract
 B-Myb is an oncoprotein involved in cell cycle gene regulation. B-Myb contacts the MuvB core of five
proteins (LIN9, LIN37, LIN52, LIN53/RBBP4, and LIN54) to form the MMB (Myb-MuvB) complex. The MMB
complex, in turn, promotes expression of late cell cycle genes for progression through mitosis. By interacting
with an alternative set of binding partners (E2F4-DP1 and p130/p107), the MuvB core can become part of the
DREAM complex (DP, RB-like, E2F, and MuvB), which opposes MMB by repressing cell cycle genes,
maintaining the cell in a quiescent state. Both MYBL2 amplification (encoding B-Myb) and over-expression of
MMB target genes are associated with cell proliferation and poor prognosis in many cancers. Furthermore,
data from The Cancer Genome Atlas supports high expression of B-Myb as a predictor of poor survival in high
grade serous ovarian carcinoma (HGSOC). However, the role of B-Myb in HGSOC is largely unstudied and the
mechanism by which B-Myb overexpression alters cellular behavior is not well understood. Interestingly, both
disruption of the DREAM complex and B-Myb overexpression result in a similar proliferative phenotype.
Additionally, when B-Myb is over-expressed, DREAM formation is diminished and MMB levels are comparable
to those of cycling cells, despite environmental cues for arrest. Therefore, to elucidate the mechanism of B-
Myb's oncogenicity, it is important to establish the effect of B-Myb on DREAM function. We hypothesize that
increased expression of B-Myb drives cell proliferation by sequestering MuvB, via binding LIN52, and
disrupting DREAM-mediated repression of cell cycle genes. To test our hypothesis, we will employ human
immortalized fallopian tube epithelial cells (FTE-hTERT stably expressing B-Myb) for gain of function studies.
We will also perform loss of function and rescue studies in SKOV3 cells (ovarian cancer cells with MYBL2
amplification) using a tet-inducible dual expression system to simultaneously deplete endogenous B-Myb and
express our ectopic protein. RT-qPCR, flow cytometry, and IP/WB will be used to measure changes in target
gene expression, cell proliferation and cell cycle profile, as well as MMB and DREAM complex formation,
respectively. Additionally, we will assess the importance of MMB formation in mediating B-Myb's oncogenic
effects by expressing a MuvB-binding deficient B-Myb mutant. To establish the relevance of our
findings to human health, we will determine the effect of B-Myb levels on DREAM target gene expression
in HGSOC tissue samples. We will relate our findings to the treatment responses and outcomes
of these patients. Overall, we seek to understand the mechanisms by which B-Myb alters the formation of cell
cycle gene regulatory complexes (DREAM and MMB), cell cycle gene expression, and promotes proliferative
cellular phenotypes in ovarian cancer. Our ultimate goal is to identify novel predictive markers and therapeutic
targets to aid in the treatment of this deva...

## Key facts

- **NIH application ID:** 9873940
- **Project number:** 5F30CA221004-03
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Audra Iness
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $35,852
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873940

## Citation

> US National Institutes of Health, RePORTER application 9873940, Mechanisms of B-Myb oncogenicity in ovarian cancer (5F30CA221004-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9873940. Licensed CC0.

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