WDHD1 is essential for the survival of PTEN-inactive triple-negative breast cancer.
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Embargo End Date
ICR Authors
Authors
Ertay, A
Liu, H
Liu, D
Peng, P
Hill, C
Xiong, H
Hancock, D
Yuan, X
Przewloka, MR
Coldwell, M
Howell, M
Skipp, P
Ewing, RM
Downward, J
Wang, Y
Liu, H
Liu, D
Peng, P
Hill, C
Xiong, H
Hancock, D
Yuan, X
Przewloka, MR
Coldwell, M
Howell, M
Skipp, P
Ewing, RM
Downward, J
Wang, Y
Document Type
Journal Article
Date
2020-11-21
Date Accepted
2020-11-05
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer that lacks the oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, making it difficult to target therapeutically. Targeting synthetic lethality is an alternative approach for cancer treatment. TNBC shows frequent loss of phosphatase and tensin homologue (PTEN) expression, which is associated with poor prognosis and treatment response. To identify PTEN synthetic lethal interactions, TCGA analysis coupled with a whole-genome siRNA screen in isogenic PTEN-negative and -positive cells were performed. Among the candidate genes essential for the survival of PTEN-inactive TNBC cells, WDHD1 (WD repeat and high-mobility group box DNA-binding protein 1) expression was increased in the low vs. high PTEN TNBC samples. It was also the top hit in the siRNA screen and its knockdown significantly inhibited cell viability in PTEN-negative cells, which was further validated in 2D and 3D cultures. Mechanistically, WDHD1 is important to mediate a high demand of protein translation in PTEN-inactive TNBC. Finally, the importance of WDHD1 in TNBC was confirmed in patient samples obtained from the TCGA and tissue microarrays with clinic-pathological information. Taken together, as an essential gene for the survival of PTEN-inactive TNBC cells, WDHD1 could be a potential biomarker or a therapeutic target for TNBC.
Citation
Cell death & disease, 2020, 11 (11), pp. 1001 - ?
Source Title
Publisher
ISSN
2041-4889
eISSN
2041-4889
Collections
Research Team
Lung Cancer Group
Lung Cancer Group
Lung Cancer Group