Functional Analysis of Potential Therapeutic Target(s) in 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 homolog (PTEN) expression, which is associated with poor prognosis and treatment response. PTEN is a tumour suppressor gene and has a role in inhibiting oncogenic AKT signalling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2).
To identify PTEN synthetic lethal interactions, TCGA analysis coupled with a whole-genome siRNA screen in isogenic PTEN-negative and -positive cells was performed. Among the candidate genes essential for the survival of PTEN-inactive TNBC cells, WD repeat and high mobility group [HMG]-box DNA binding protein 1 (WDHD1) expression was increased in the low vs. high PTEN TNBC samples. It was also the top hit in the siRNA screen. Knockdown of WDHD1 significantly inhibited cell viability in PTEN-negative cells, which was further validated in 2D and 3D cultures. We also showed that PTEN status affects the expression of WDHD1 in TNBC cells via AKT signalling. The importance of WDHD1 in TNBC was confirmed in patient samples obtained from the TCGA and tissue microarrays with clinicopathological information. Mechanistically, WDHD1 is important for cell cycle progression as well as mediating a high demand of protein translation in PTEN-inactive TNBC via directly interacting with the components of translation machinery.
Taken together, this study demonstrated that WDHD1 expression is regulated by the PTEN/AKT signalling pathway and it has an impact on cell cycle and protein translation in TNBC. Thus, as an essential gene for the survival of PTEN-inactive TNBC cells, WDHD1 could be a potential therapeutic target for TNBC.

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Identifiers

ORCID for Yihua Wang: orcid.org/0000-0001-5561-0648

ORCID for Robert Ewing: orcid.org/0000-0001-6510-4001

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