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Updated: Feb 24, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Mitotic Vulnerability in Triple-Negative Breast Cancer Associated with LIN9 Is Targetable with BET Inhibitors
Jennifer M Sahni1, Sylvia S Gayle1, Bryan M Webb1
1Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio.
Abstract:
Triple-negative breast cancers (TNBC) are highly aggressive, lack FDA-approved targeted therapies, and frequently recur, making the discovery of novel therapeutic targets for this disease imperative. Our previous analysis of the molecular mechanisms of action of bromodomain and extraterminal protein inhibitors (BETi) in TNBC revealed these drugs cause multinucleation, indicating BET proteins are essential for efficient mitosis and cytokinesis. Here, using live cell imaging, we show that BET inhibition prolonged mitotic progression and induced mitotic cell death, both of which are indicative of mitotic catastrophe. Mechanistically, the mitosis regulator LIN9 was a direct target of BET proteins that mediated the effects of BET proteins on mitosis in TNBC. Although BETi have been proposed to function by dismantling super-enhancers (SE), the LIN9 gene lacks an SE but was amplified or overexpressed in the majority of TNBCs. In addition, its mRNA expression predicted poor outcome across breast cancer subtypes. Together, these results provide a mechanism for cancer selectivity of BETi that extends beyond modulation of SE-associated genes and suggest that cancers dependent upon LIN9 overexpression may be particularly vulnerable to BETi. Cancer Res; 77(19); 5395-408. ©2017 AACR.
Insights
Bromodomain and extraterminal protein inhibitors (BETi) cause mitotic catastrophe in triple-negative breast cancer (TNBC) by targeting the cell division regulator LIN9. This finding offers a new therapeutic strategy for TNBC by exploiting LIN9 dependency.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Triple-negative breast cancer (TNBC) is aggressive, lacks targeted therapies, and has high recurrence rates.
- Bromodomain and extraterminal protein inhibitors (BETi) induce multinucleation in TNBC, suggesting a role in mitosis and cytokinesis.
- Discovering novel therapeutic targets for TNBC is crucial.
Purpose of the Study:
- To investigate the mechanism by which BET inhibitors affect mitosis in TNBC.
- To identify specific molecular targets of BET proteins in TNBC mitosis.
- To explore the therapeutic potential of targeting LIN9 in TNBC.
Main Methods:
- Live cell imaging to observe mitotic progression and cell death.
- Analysis of LIN9 as a direct target of BET proteins.
- Examination of LIN9 gene expression and its correlation with patient outcomes.
Main Results:
- BET inhibition prolongs mitotic progression and induces mitotic cell death (mitotic catastrophe) in TNBC.
- LIN9 was identified as a direct target of BET proteins, mediating their effects on mitosis.
- LIN9 lacks super-enhancers but is overexpressed in most TNBCs, and its expression predicts poor outcomes.
Conclusions:
- BET inhibitors induce mitotic catastrophe in TNBC through LIN9 regulation, independent of super-enhancer modulation.
- LIN9 overexpression confers vulnerability to BET inhibitors in TNBC.
- Targeting LIN9-dependent cancers with BETi represents a promising therapeutic strategy.
