Molecular mechanism of BQ323636.1, a novel splice variant of NCOR2 and its significance on treatment of estrogen receptor positive breast cancer.
Grant Data
Project Title
Molecular mechanism of BQ323636.1, a novel splice variant of NCOR2 and its significance on treatment of estrogen receptor positive breast cancer.
Principal Investigator
Professor Khoo, Ui Soon
(Principal Investigator (PI))
Co-Investigator(s)
Dr Tsoi Ho
(Co-Investigator)
Duration
30
Start Date
2020-07-01
Completion Date
2022-12-31
Amount
996285
Conference Title
Molecular mechanism of BQ323636.1, a novel splice variant of NCOR2 and its significance on treatment of estrogen receptor positive breast cancer.
Keywords
breast cancer, drug resistance, splice variant of NCOR2, splicing factor SRSF5
Discipline
CancerMolecular Biology
Panel
Biology and Medicine (M)
HKU Project Code
17113020
Grant Type
General Research Fund (GRF)
Funding Year
2020
Status
Completed
Objectives
1 To elucidate the molecular mechanism of BQ synthesis, thus identify potential targets for reducing BQ production (a) by using siRNA or small inhibitors to ATM, ATR, DNA-protein kinase (b) by using siRNA or small inhibitors to their down-stream targets CHK1, CHK2 and serine/threonine-protein kinase SRPK1 2 To perform biochemical analyses to demonstrate how BQ binds to NCOR2 to compromise the formation of functional co-repressor complex. (a) To demonstrate by pull down assay the direct binding of BQ to NCOR2. (b) To use deletion mutants to identify the region(s) on NCOR2 responsible for interacting with BQ. (c) To demonstrate by immunoprecipitation the formation of NCOR2 dimer can be compromised in a BQ dose dependent manner. 3 To use in vivo models to validate the functional significance of SRSF5 in contributing to tamoxifen resistance. (a) Using mouse xenograft model to confirm the effect of SRSF5 knockout in (i) modulating BQ expression, and (ii) developing tamoxifen resistance. (b) Using clinical tissue samples of ER+ve breast cancer patients in tissue microarray to (i) demonstrate inverse correlation between SRSF5 and BQ expression in breast cancer tumor samples, and (ii) correlate SRSF5 expression with clinical outcome. 4 To demonstrate that depletion of SRSF5 in ER+ve breast cancer cells can lead to (a) activation of the cAMP, CaMKII and Ras signaling pathways, with (b) the proliferative pathway predominating over that of apoptosis.