Related Experiment Video
Updated: Jul 4, 2025
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
The novel phosphatase NUDT5 is a critical regulator of triple-negative breast cancer growth
Jing Qian1,2, Yanxia Ma1,3, William M Tahaney1,4,5
1Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Background:
The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the human epidermal growth factor receptor 2 (HER2). Treatment options for women with TNBC tumors are limited, unlike those with ER-positive tumors that can be treated with hormone therapy, or those with HER2-positive tumors that can be treated with anti-HER2 therapy. Therefore, we have sought to identify novel targeted therapies for TNBC. In this study, we investigated the potential of a novel phosphatase, NUDT5, as a potential therapeutic target for TNBC.
Methods:
The mRNA expression levels of NUDT5 in breast cancers were investigated using TCGA and METABRIC (Curtis) datasets. NUDT5 ablation was achieved through siRNA targeting and NUDT5 inhibition with the small molecule inhibitor TH5427. Xenograft TNBC animal models were employed to assess the effect of NUDT5 inhibition on in vivo tumor growth. Proliferation, death, and DNA replication assays were conducted to investigate the cellular biological effects of NUDT5 loss or inhibition. The accumulation of 8-oxo-guanine (8-oxoG) and the induction of γH2AX after NUDT5 loss was determined by immunofluorescence staining. The impact of NUDT5 loss on replication fork was assessed by measuring DNA fiber length.
Results:
In this study, we demonstrated the significant role of an overexpressed phosphatase, NUDT5, in regulating oxidative DNA damage in TNBCs. Our findings indicate that loss of NUDT5 results in suppressed growth of TNBC both in vitro and in vivo. This growth inhibition is not attributed to cell death, but rather to the suppression of proliferation. The loss or inhibition of NUDT5 led to an increase in the oxidative DNA lesion 8-oxoG, and triggered the DNA damage response in the nucleus. The interference with DNA replication ultimately inhibited proliferation.
Conclusions:
NUDT5 plays a crucial role in preventing oxidative DNA damage in TNBC cells. The loss or inhibition of NUDT5 significantly suppresses the growth of TNBCs. These biological and mechanistic studies provide the groundwork for future research and the potential development of NUDT5 inhibitors as a promising therapeutic approach for TNBC patients.
Insights
Targeting NUDT5, a phosphatase overexpressed in triple-negative breast cancer (TNBC), suppresses tumor growth by increasing oxidative DNA damage and inhibiting proliferation. This identifies NUDT5 as a potential therapeutic target for TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options due to the absence of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression.
- Current treatments for TNBC are less effective compared to hormone- or HER2-targeted therapies available for other breast cancer subtypes.
- There is a critical need for novel targeted therapies to improve outcomes for TNBC patients.
Purpose of the Study:
- To investigate the phosphatase NUDT5 as a potential therapeutic target for triple-negative breast cancer (TNBC).
- To elucidate the role of NUDT5 in the regulation of oxidative DNA damage within TNBC cells.
- To assess the impact of NUDT5 inhibition on TNBC cell proliferation and tumor growth.
Main Methods:
- NUDT5 mRNA expression was analyzed in breast cancer datasets (TCGA, METABRIC).
- NUDT5 was inhibited using siRNA and a small molecule inhibitor (TH5427) in vitro and in vivo (xenograft models).
- Cellular assays measured proliferation, death, and DNA replication; DNA damage markers (8-oxoG, γH2AX) and DNA fiber length were assessed.
Main Results:
- NUDT5 is significantly overexpressed in TNBC and plays a key role in managing oxidative DNA damage.
- Loss or inhibition of NUDT5 suppressed TNBC growth in vitro and in vivo, primarily by reducing proliferation, not increasing cell death.
- NUDT5 inhibition led to increased oxidative DNA lesions (8-oxoG), triggered DNA damage responses, and interfered with DNA replication.
Conclusions:
- NUDT5 is essential for preventing oxidative DNA damage and maintaining proliferation in TNBC cells.
- Inhibition of NUDT5 effectively suppresses TNBC growth through mechanisms involving DNA damage and replication interference.
- NUDT5 represents a promising therapeutic target for developing novel treatment strategies for triple-negative breast cancer.
Related Concept Videos
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:22PI3K/mTOR/AKT Signaling Pathway
01:23Negative Regulator Molecules
02:23Abnormal Proliferation
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:55The Nucleolus