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Updated: Jul 4, 2025
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Blocking LBH expression causes replication stress and sensitizes triple-negative breast cancer cells to ATR inhibitor
Koteswararao Garikapati1,2, In-Chi Young1,2, Sunhwa Hong1,2
1DeWitt Daugherty Department of Surgery, Molecular Oncology Program, University of Miami Miller School of Medicine, Miami, FL, USA.
Abstract:
Triple-negative (ER-PR-HER2-) breast cancers (TNBC) are highly aggressive and difficult to treat. TNBC exhibit high genomic instability, which enables them to adapt and become resistant to chemo/radiation therapy, leading to rapid disease relapse and mortality. The pro-survival factors that safeguard genome integrity in TNBC cells are poorly understood. LBH is an essential mammary stem cell-specific transcription regulator in the WNT pathway that is aberrantly overexpressed in TNBC, correlating with poor prognosis. Herein, we demonstrate a novel role for LBH in promoting TNBC cell survival. Depletion of LBH in multiple TNBC cell models triggered apoptotic cell death both in vitro and in vivo and led to S-G2M cell cycle delays. Mechanistically, LBH loss causes replication stress due to DNA replication fork stalling, leading to ssDNA breaks, ɣH2AX and 53BP1 nuclear foci formation, and activation of the ATR/CHK1 DNA damage response. Notably, ATR inhibition in combination with LBH downmodulation had a synergistic effect, boosting TNBC cell killing and blocking in vivo tumor growth. Our findings demonstrate, for the first time, that LBH protects the genome integrity of cancer cells by preventing replicative stress. Importantly, they uncover new synthetic lethal vulnerabilities in TNBC that could be exploited for future multi-modal precision medicine.
Insights
LBH protein loss triggers cancer cell death in triple-negative breast cancer (TNBC). Combining LBH depletion with ATR inhibitors offers a new precision medicine strategy for aggressive TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) is aggressive, characterized by genomic instability and resistance to therapy.
- Pro-survival factors maintaining genome integrity in TNBC are not well understood.
- LBH, a WNT pathway regulator overexpressed in TNBC, correlates with poor prognosis.
Purpose of the Study:
- To investigate the role of LBH in TNBC cell survival and genome integrity.
- To identify novel therapeutic vulnerabilities in TNBC based on LBH function.
Main Methods:
- Depletion of LBH in TNBC cell models (in vitro and in vivo).
- Analysis of cell death, cell cycle progression, and DNA damage markers (ssDNA, ɣH2AX, 53BP1).
- Assessment of the ATR/CHK1 DNA damage response pathway.
- Combination therapy studies with LBH depletion and ATR inhibitors.
Main Results:
- LBH depletion induced apoptosis and S-G2M cell cycle arrest in TNBC cells.
- LBH loss led to replication stress, DNA fork stalling, and activation of the ATR/CHK1 pathway.
- Combined LBH downmodulation and ATR inhibition synergistically enhanced TNBC cell killing and inhibited tumor growth.
Conclusions:
- LBH is crucial for maintaining genome integrity in TNBC by preventing replicative stress.
- Targeting LBH and the ATR pathway presents a promising synthetic lethal strategy for TNBC treatment.
- This study uncovers new therapeutic vulnerabilities for precision medicine in aggressive breast cancers.
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