WDHD1 is essential for the survival of PTEN-inactive triple-negative breast cancer

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.

Integrated analysis reveals effects of bioactive ingredients from Limonium Sinense (Girard) Kuntze on hypoxia-inducible factor (HIF) activation

“…Sources of cell lines and culture conditions were reported earlier ( Wang et al., 2014 ; Liu et al., 2019 ; Ertay et al., 2020 ). Details are provided in the Supplementary Methods .…”

“…Mammosphere assay and quantifications were performed as previously described ( Ertay et al., 2020 ). Details are provided in the Supplementary Methods .…”

“…Western blot analysis was performed as previously described ( Hill et al., 2019 ; Wang et al., 2019 ; Yao et al., 2019 ; Ertay et al., 2020 ). Details are provided in the Supplementary Methods .…”

Identification of Survival-Associated Hub Genes in Pancreatic Adenocarcinoma Based on WGCNA

“…WDHD1 has also been reported to facilitate the abrogation of G1 checkpoint upon DNA damage, leading to genomic instability and eventually tumorigenesis ( Zhou et al, 2020 ). Moreover, WDHD1 could accelerate cell proliferation, cell viability, and metastasis in several cancers including cholangiocarcinoma and breast cancer ( Sato et al, 2010 ; Liu et al, 2019 ; Ertay et al, 2020 ; Zhou and Chen, 2021 ). In accordance with the above research, both our overall and disease free survival analysis exhibited that high levels of WDHD1 correlated with poor patient outcome ( Figures 4B , 5B ), confirming the oncogenic function of WDHD1 in pancreatic adenocarcinoma and expanding it roles in cancer biology which need further validations.…”

PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer

“…Among patients receiving neoadjuvant regimens containing docetaxel, carboplatin, trastuzumab and lapatinib, those with tumors with PIK3CA/ERBB family mutations seem to develop pathologic complete response (pCR) more than those with wild-type tumors [ 55 ]. For TNBC, the most common abnormal mechanism of PAM is PTEN inactivation or downregulation, accounting for 67% of cases [ 56 , 57 ]. In addition, mTOR hyperphosphorylation is associated with poor outcomes of patients with stage I/II TNBC [ 46 ].…”