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Functional Analysis of Potential Therapeutic Target(s) in PTEN-inactive Triple Negative Breast Cancer

Functional Analysis of Potential Therapeutic Target(s) in PTEN-inactive Triple Negative Breast Cancer
Functional Analysis of Potential Therapeutic Target(s) in PTEN-inactive Triple Negative Breast Cancer
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.
University of Southampton
Ertay, Ayse
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Ertay, Ayse
fdd0c5cb-cfb2-4e25-9343-cdc462035531
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Ewing, Robert
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Ertay, Ayse (2022) Functional Analysis of Potential Therapeutic Target(s) in PTEN-inactive Triple Negative Breast Cancer. University of Southampton, Doctoral Thesis, 239pp.

Record type: Thesis (Doctoral)

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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Published date: 18 March 2022

Identifiers

Local EPrints ID: 455361
URI: http://eprints.soton.ac.uk/id/eprint/455361
PURE UUID: 785b3d3c-4a59-4b7b-bb05-8b4391448c35
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648
ORCID for Robert Ewing: ORCID iD orcid.org/0000-0001-6510-4001

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Date deposited: 18 Mar 2022 17:32
Last modified: 23 Jul 2022 02:11

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Contributors

Author: Ayse Ertay
Thesis advisor: Yihua Wang ORCID iD
Thesis advisor: Robert Ewing ORCID iD

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