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Singh, Youvica (2025) Targeting DNA damage repair pathways in breast and ovarian cancers. MPhil thesis, University of Nottingham.

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Abstract

Background

DNA damage could be due to many endogenous and exogenous agents producing DNA lesions which block the transcription process affecting the gene expression, cell growth and survival. The DNA damage response network detects the damage and any flaw in the network including defects in DNA repair systems can lead to cancer. Thus, drugs targeting DNA repair systems relying on this concept are under development with various drug monotherapy or combination therapies. Targeting DNA repair genes of nucleotide excision repair system (XAB2) and Fanconi anaemia repair system (FANCD2 and FANCA) for synthetic lethality is a novel strategy for treating breast and ovarian cancers. Hence, the synthetic lethality concept is an exciting area for future research.



Methods

In this study, XAB2 expression in the breast cancer cohort was investigated. Cisplatin and olaparib sensitivity was evaluated in a panel of gene XAB2, FANCD2, FANCA deficient and proficient breast and ovarian cancer cell lines. XAB2 expression and the clinicopathological outcomes were investigated in the ovarian cancer cohort. The gene knockdown and cisplatin sensitivity were tested in platinum-sensitive and platinum-resistant ovarian and breast cancer cell lines. Functional studies for wild and knockdown genes such as PI FACS-cell cycle and Annexin V-apoptosis assay were performed.



Results

In breast cancer cases, results showed that a low XAB2 nuclear expression was associated with a high tumour grade and poor breast cancer-specific survival (BCSS) in patients. In invasive breast cancer, low XAB2 expression had clinicopathological associations with aggressive forms of breast cancer.

In gene knockdown, cisplatin and olaparib were synthetically lethal in gene-deficient breast cancer cell lines. In ovarian cancers, XAB2 was significantly overexpressed in serous adenocarcinoma. The low XAB2 expression was significantly linked to good overall survival. The cisplatin was selectively toxic in gene-deficient platinum-sensitive ovarian cancer cell lines. The drug cytotoxicity was associated with double-strand breaks (DSBs) formation, cell cycle arrest and apoptosis in gene-deficient cells. The gene expression was a predictor of platinum sensitivity in ovarian cancer patients. The gene knockdown not only increased platinum sensitivity but also reduced invasion and migration in breast and ovarian cancer cell lines. The cisplatin drug was selectively toxic in gene-deficient breast and ovarian cancer cells.

Conclusion

Targeting DNA repair genes was an attractive synthetic lethality strategy and the chemoprevention in gene-deficient breast cancers. In ovarian cancers, gene deficiency was a biomarker for drug inhibitor sensitivity. It provided alternative synthetic lethality approaches for inhibitors in clinics. The gene depletion can re-sensitize ovarian cancer patients to platinum. Therefore, studying the expression of DNA repair proteins assisted in new drug therapies development and opened alternative treatment options.

Item Type:	Thesis (University of Nottingham only) (MPhil)
Supervisors:	Madhusudan, Srinivasan Rakha, Emad
Keywords:	DNA damage response (DDR); Synthetic lethality; Fanconi anemia pathway DNA repair genes
Subjects:	QS-QZ Preclinical sciences (NLM Classification) > QZ Pathology W Medicine and related subjects (NLM Classification) > WP Gynecology
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	80316
Depositing User:	SINGH, YOUVICA
Date Deposited:	23 Jul 2025 04:40
Last Modified:	23 Jul 2025 04:40
URI:	https://eprints.nottingham.ac.uk/id/eprint/80316

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