Saudi Cultural Missions Theses & Dissertations
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Item Restricted A Comparison of POSH and UK Biobank Data in Young-onset Breast Cancer(Saudi Digital Library, 2025) ALABDULRAZAQ, OHOUD; Tapper, WilliamFor young women, a breast cancer diagnosis often marks the beginning of a particularly difficult journey. Their cancers are typically more aggressive, harder to treat, and more likely to recur in the opposite breast. Yet the genetic risk prediction tools we use (Polygenic Risk Scores (PRS)) were mostly developed using data from older, postmenopausal women. As a result, they are less effective for younger patients, leaving a critical gap in care. My research aimed to address this gap by assessing how well current PRS perform in young- onset breast cancer (YOBC) and by exploring genetic factors that may be unique to this group. I conducted a genome-wide association study (GWAS), comparing YOBC cases from the Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) with healthy controls from the UK Biobank. However, direct comparisons between these heterogeneously genotyped cohorts showed inflated test statistics and possible technical artifacts. To overcome this, I carried out a UK Biobank-only analysis, which identified 159 genome-wide significant SNPs. I also evaluated the widely used PRS313 model in YOBC. While it provided some population- level risk stratification, its individual predictive accuracy was modest (AUC = 0.59), highlighting its limited utility for younger women. These findings underscore the need for PRS specifically tailored to YOBC. Developing age- specific models that capture the unique genetic architecture and aggressive biology of these cancers could improve early detection, enable more personalised treatment strategies, and ultimately enhance survival and quality of life. This work represents an important step toward ensuring that young women receive accurate risk predictions and the care they deserve.15 0Item Restricted Characterizing Immune and Epithelial Biomarkers in Triple-Negative Breast Cancer (TNBC) Progression Using the KBP Mouse Model.(Saudi Digital Library, 2025) Almoteriy, Rimas; Chiara, Gorrini; Erica, WillsonTriple-negative breast cancer (TNBC) is a heterogeneous and aggressive subtype of breast cancer with limited therapies currently available due to the lack of targeted receptors. Macrophages and epithelial tumor cells, which are key cells present in the tumor microenvironment, have been acknowledged to play a significant role in disease progression and metastasis. The study aims to identify the tumor-immune biomarkers that contribute to cancer aggressiveness in a well-established K14cre; BRCA1^f/f; p53^f/f (KBP) TNBC mouse model that resembles aggressive human TNBC. Histological analysis showed abnormal cellular morphology, and CK14 immunohistochemical and immunofluorescence staining confirmed the basal-like epithelial characteristics across primary, early, and late metastatic sites, whereas CD68 immunohistochemical and immunofluorescence staining demonstrated macrophage infiltration with focal infiltration in early metastasis and widespread macrophage infiltration in late metastasis. Gene expression studies displayed differential expression of the following cytokines: CCL2 and CXCL5, which are involved in macrophage and neutrophil recruitment. Nonetheless, the project’s results illustrate the dynamic role of the immune microenvironment in the progression of TNBC and propose opportunities for developing therapeutics.7 0Item Restricted Overcoming doxorubicin resistance in triple-negative breast cancer with novel mPEG-PCL-DOX nanoparticles(Saudi Digital Library, 2025) Alnaeem, Ahmed; Allegrucci, Cinzia; Alexander, Cameron; Grabowska, Anna; Paine, StuartTriple-negative breast cancer (TNBC) is an aggressive subtype characterised by the absence of estrogen, progesterone, and human epidermal growth factor receptors, limiting the use of targeted therapies clocking these proteins. Chemotherapy is still the first line treatment for TNBC and Doxorubicin (DOX) is a commonly used drug, but its effectiveness is limited by dose-dependent cardiotoxicity and multidrug resistance (MDR), often mediated by P-glycoprotein (PgP) efflux. This thesis focused on developing novel pH-responsive methoxy-poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) nanoparticles conjugated with doxorubicin (mPEG-PCL-DOX) via azide–alkyne click chemistry as a new drug delivery system to overcome resistances. The nanoparticles synthesis showed stability at physiological pH with accelerated drug release under acidic conditions. In MDA-MB-231 TNBC cells and resistant derivatives (acquired DOX-resistant and PgP-overexpressing models), mPEG-PCL-DOX showed slower but sustained cytotoxicity compared with free DOX, with improved intracellular accumulation. Importantly, in 3D spheroid models incorporating basement membrane extract to mimic tumour hypoxia, acidosis, and ECM barriers, mPEG-PCL-DOX showed superior penetration compared with free DOX, particularly in resistant spheroids. These findings demonstrate the ability of pH-responsive polymer–drug conjugates to use the acidic TME, overcome efflux-based resistance, and enhance therapeutic performance in physiologically relevant models. Overall, this work highlights mPEG-PCL-DOX nanoparticles as a promising strategy to improve the efficacy and safety of DOX in TNBC. While current results are based on in vitro studies, they provide a strong ground for in vivo evaluation of biodistribution, pharmacokinetics, therapeutic efficacy, and toxicity. This platform may also be adapted to the use of alternative drugs in breast cancer subtypes where DOX is not standard treatment, supporting its broader application in precision nanomedicine.12 0Item Restricted Role of LaNt α31 in breast cancer(Saudi Digital Library, 2025) Asiri, Fawziah; Hamill, KevinInvasion and metastasis of tumour cells are complex processes involving the interaction of cancer cells with laminins and other extracellular matrix components. Laminin N-terminus α31 is a laminin-derived, netrin-like protein produced by alternative splicing from the LAMA3 gene. To date, LaNt α31 has been established to be expressed in most tissues and is upregulated in breast cancer, with further upregulation in distal metastases. In addition, cell culture studies have established that LaNt α31 overexpression alters the mode of MDAMB231 breast cancer cell invasion from multicellular streaming to individual cell invasion when invading a laminin-containing matrix. However, no further experiments have been reported beyond these observations, leaving a substantial gap in knowledge. This thesis describes investigations designed to increase understanding of the mechanisms driving LaNt α31-induced changes and to determine the impact on cancer cell behaviour, including invasion and migration. Firstly, LaNt α31 was overexpressed using adenoviral-mediated transduction in invasive and non-invasive breast cancer cell lines. The effects of LaNt α31 on the activity of crucial cell signalling cascades known to modulate matrix remodelling and invasive behaviour and be regulated by laminin-mediated signalling, including FAK, SRC, and PI3K/AKT, were assessed by western blot and antibody arrays targeting phosphorylated protein kinases. These analyses revealed that the upregulation of LaNt α31 led to a sustained increase in Akt phosphorylation, with less pronounced changes observed in the other pathways. RNA sequencing was used to explore changes in the expression of genes that influence matrix remodelling, integrity, and adhesion as a consequence of induced LaNt α31 expression. Elevated mRNA expression of laminin α3, β3, and γ2 subunits was observed in both cell lines . Collagens that anchor laminins to the matrix, including basement membrane collagen IV and anchoring fibril collagen VII, were elevated in invasive breast cancer cell lines. In addition, the genes for proteins involved in hemidesmosomes, focal adhesion, desmosomes, and tight junctions were increased in MDAMB231-LaNt α31 . The expression of the major receptors and co-receptors that bind to either laminins or collagens, such as integrins α2, α3, α5, α6, and β1, was also increased. To perform longer-term experiments, including three-dimensional (3D) culture and impedance-based cell analysis , lentiviral expression was used to drive stable expression. 3D cultures were conducted to study the invasive behaviour of LaNt α31-expressing cells in a tumour microenvironment model. In this assay, laminin-enriched matrix (Matrigel) and collagen I were used as substrates, with assays performed in the presence or absence of pathway inhibitors. The results demonstrated that MDA-MB-231-LaNt α31 cells assembled compact, aggregated spheroids when embedded in a collagen I matrix. In contrast, in laminin-containing matrices, LaNt α31 induced ductal-like tube formation resembling a process known as vasculogenic mimicry, with increased central core sizes. Targeting the PI3Ks and MMPs impaired the observed effects of LaNt α31 expression in spheroids, but not those of ROCK inhibitors consistent with the requirement of PI3K/AKT pathway activation for these outcomes. Impedance-based phenotypic assays were performed using various substrate coatings, including media secreted from untreated cells, media from LaNt α31-expressing cells, or from purified extracellular matrix proteins LM111, LM511, LM332, rat tail collagen I, or netrin-4. These studies identified that MDAMB231-LaNt α31 cells increased barrier function and covered the electrodes more quickly than MDAMB231-WT. Interestingly, the coverage and barrier integrity of MDAMB231-untreated and MDAMB231-LaNt α31 cells on plates coated with either netrin-4 or conditioned media from LaNt α31-expressing cells were very similar. Together, these results reveal that LaNt α31 induces clustering, cell-cell interaction, and proliferation in invasive breast cancer cell lines in 2D and 3D environments by enhancing LM332 levels alongside α6β1 and α3β1 integrins, co-receptors, and adhesion protein-mediated signalling pathways. Furthermore, increased expression of LaNt α31 is linked to altered cellular behaviour in tumour microenvironment models potentially driven by and dependent on modulation of the PI3K/Akt signalling pathway leading to a hypoxic-like state and vascular mimicry in invasive breast cancer cells. These findings identify a complex interplay between LaNt α31, molecular signals, and extracellular matrix proteins that contribute to breast cancer proliferation and invasive behaviour. This research has implications for understanding LaNt α31 and laminin-mediated regulation of tumour progression.21 0Item Restricted Breast Cancer Treatment Disparities in Patients with Severe Mental Illness: A Systematic Review and Meta-Analysis(Queensland University of Technology, 2024) Alotiby, Meshary; Protani, Melinda; Kisely, Steve; Siskind, DanBackground Disparities in breast cancer treatment for people with pre-existing severe mental illness (SMI) have not been well studied compared to disparities in cancer screening and stage at diagnosis. Aims To conduct a systematic review of the available evidence and investigate whether female breast cancer patients with pre-existing SMI had equitable access to guideline recommended breast cancer treatment compare to those without SMI. Methods We conducted systematic review and meta-analysis of observational studies that were retrieved from PubMed, EMBASE, CINAHL and PsycINFO databases from 22 February 2021 to 26 March 2021. Female breast cancer patients with SMI were included in the analyses. SMI was defined as Schizophrenia, Bipolar disorder, and major depression. Guideline recommended treatment was defined as surgery, chemotherapy, radiotherapy and adjuvant endocrine therapy. Pooled odds ratios, and other estimates, such as hazard ratios and risk ratios were presented. Risk of bias was assessed using Newcasle-Ottawa scale. DerSimonian-Laird random effects models were used. Results 3,325 citations were identified; 10 studies were included, and 4 studies were meta-analysed. Pooled analyses suggested that people with SMI were less likely to receive guideline recommended breast cancer treatment than those without SMI (OR: 0.83; 95% CI: 0.77 to 0.90). Breast cancer patients with schizophrenia had a reduced likelihood for receiving adjuvant radiotherapy (Crude RR: 0.81, 95% CI: 0.77 to 0.85), while those with major depression and bipolar I disorder had lower likelihood of receiving adjuvant chemotherapy (Crude RR: 0.71, 95% CI: 0.60 to 0.84). Conclusions This review identified disparities in breast cancer care for individuals with pre-existing SMI, which contributed to poorer prognosis and excess mortality. Improving collaboration between psycho-oncology teams is advised to address patients’ needs for treatment. Future research is necessary for identifying disparities in primary and systemic treatments and investigating the reasons for treatment inequity.11 0Item Restricted Optimizing Deep Learning Architectures for Enhanced Breast Cancer Detection on Mammography Images(University of Liverpool, 2024) Albalawi, Alaa; Anosova, OlgaBreast cancer is a major health issue affecting millions of women globally, and early detection through mammography is critical for improving survival rates. However, mammography often faces challenges, such as imbalanced datasets and poor image quality, especially in dense breast tissue, which complicates accurate detection. This project explores the use of deep learning techniques, including Convolutional Neural Networks (CNNs) and Vision Transformers (ViTs), to address these challenges and enhance breast cancer detection. Five models—ResNet50V2, MobileNetV2, VGG16, ResNet from scratch, and ViT—were compared using various evaluation metrics. Two datasets, RSNA and MIAS, were used, with preprocessing applied only to the RSNA dataset. The experiments were divided into three stages: the first stage evaluated the original RSNA dataset without preprocessing, the second stage tested the balanced and preprocessed RSNA dataset with and without data augmentation, and the third stage applied similar experiments on the MIAS dataset. The results showed that preprocessing and balancing the RSNA dataset significantly improved model performance, while data augmentation further enhanced accuracy and generalization. ViT models outperformed other CNN architectures, demonstrating superior detection abilities after augmentation. ResNet from scratch also showed strong results, benefiting from its controlled architecture that adapted well to high-resolution images. This study highlights how addressing class imbalance and optimising model architectures can lead to more effective breast cancer detection using deep learning.25 0Item Restricted Mathematical Modelling of Breast Cancer Cells – Immun System Interaction with the Effect of Time Delay and Glucose Treatment(Universiti Teknologi Malaysia, 2024-06-04) Alblowy, Abeer Hamdan H; Maan, NormahThe proliferation and uncontrollable growth of tumor cells during immune system interaction are aided by insufficient oxygen in the tumor microenvironment. This leads to increased glucose uptake by tumors to support energy-providing glycolysis. Hence, there is a need to investigate mathematically how glucose risk factors promote breast cancer in the dynamics of normal cells, tumor cells, and the immune system. This understanding is essential for identifying optimal treatment strategies for breast cancer. Therefore, this research proposes a mathematical model of the interaction of breast cancer cells with immune and normal cells with the impact of glucose risk factors. The model analysis provides the stability conditions for the equilibrium points and indicates the occurrence of bifurcation, considering glucose as the bifurcation parameter. Numerical results indicate uncontrollable growth of tumor and normal cells, and suppression of immune cells when the glucose is excessive which follows the theoretical findings. Additionally, the model also incorporates a time delay to account for biological processes in tumor-immune system interaction, such as cytokine secretion by immune cells targeting tumors and the production of immunosuppressive cytokines by the tumors. Biomedical evidence suggests these processes have a delayed manifestation, explaining the asymptomatic characteristic of breast cancer. The stability analysis of the delay-incorporated model reveals that the coexisting equilibrium point becomes unstable as the time delay increases, with time delay acting as the bifurcation parameter. Furthermore, Sodium-Glucose Co-Transporters 2 (SGLT-2) inhibitors are added to the delay model to explore their potential in reducing glucose’s impact on tumor growth and immune cell suppression, assessing their effectiveness against breast cancer. The analysis of the delay model with treatment is conducted using the Lyapunov function. The findings have demonstrated the efficacy of SGLT-2 inhibitors in treating breast cancer. However, to find the best drug usage conditions and prevent problems, optimal dosage is calculated with optimal control theory. This reveals a unique optimal dosage without adverse effects, where the drug ingestion rate matches the digestion rate. In conclusion, this research has demonstrated that glucose is considered a risk factor for breast cancer, and the SGLT-2 inhibitor drug may hold potential for future breast cancer therapy.47 0Item Restricted Evaluation of Replication Protein A (RPA) as a Prognostic and Therapeutic Target in Breast and Ovarian Cancer(University of Nottingham, 2024-02-14) Algethami, Mashael Abdulaziz; Madhusudan, SrinivasanIntroduction: Replication protein A is a heterotrimeric complex composed of three linked subunits encoded by unique genes: RPA1 (chromosome 17p13, 70 kDa), RPA2 (chromosome 1p36.11, 32 kDa), and RPA3 (chromosome 7p13.3, 14 kDa). RPA is a critical ssDNA binding protein that coats and protects exposed ssDNA from endogenous nucleases during repair. RPA is essential for DNA replication, repair, and recombination. The oligosaccharide/oligonucleotide binding fold (OB-fold) is an integral structural and functional component of RPA. RPA consists of a series of OB-folds (Domains A-F). In the RPA complex, RPA1 contains four ssDNA-binding domains (DBD): A, B, C, and F. These domains are responsible for most of the DNA binding activity of the complex. Both RPA2 and RPA3 contain a single DNA-binding domain and are involved in DNA binding. To understand the role of RPA in the pathogenesis of breast and ovarian cancer, we conducted a comprehensive transcriptomic, proteomic and preclinical study. Patients and methods: RPA1, RPA2, and RPA3 protein expression were evaluated in 4221 primary invasive breast carcinomas and 776 breast ductal carcinoma in situ (DCIS) specimens using immunohistochemistry. Transcriptomic investigations were completed using the METABRIC cohort (n=1980). RPA1, RPA2, and RPA3 protein expression were also evaluated in 331 cases of epithelial ovarian cancer (EOC). Transcriptomic investigations were completed using a publicly available online gene expression dataset of 1259 patients with ovarian cancer. Cisplatin and PARP1 inhibitor (PARPi) sensitivity were tested in RPA-deficient breast and ovarian cancer cell lines. Results: Loss of RPA1, RPA2, and RPA3 are frequent in DCIS and linked to aggressive features including high grade and ER and PR negativity. Low RPA was also associated with poor local recurrence-free survival in DCIS. In invasive breast cancer, low RPA1, low RPA2, and low RPA3 were all associated with larger tumour size, lympho-vascular invasion, higher histological grade, high stage, ER negativity, and poor breast cancer specific survival. Pre-clinically, RPA deficient breast cancer cells were more sensitive to cisplatin therapy compared to control cells. Additionally, the PARP1 inhibitor was synthetically lethal in RPA1- and RPA2-deficient cells compared to controls. Increased Olaparib sensitivity was associated with double strand breaks, cell cycle arrest, and increased apoptosis. In ovarian cancer, overexpression of RPA was associated with aggressive clinicopathological characteristics in EOC. In addition, high RPA expression was associated with a poor prognosis in platinum-sensitive ovarian tumours. Pre-clinical assessment showed that basal levels of RPA1 and RPA2 were higher in cisplatin-resistant A2780cis and PEO4 cells compared to cisplatin-sensitive A2780 and PEO1 cells. Additionally, depletion of RPA1 and RPA2 caused substantial platinum sensitization and increased PARP inhibitor sensitivity in A2780cis and PEO4 cells compared to control cells; this increased sensitivity was associated with increased accumulation of double strand breaks, S-phase cell cycle arrest, and apoptotic cells. Conclusions: We provide the first comprehensive evidence that loss of RPA is an early event in the pathogenesis of breast cancer and promotes aggressive phenotypes. Pre-clinically, cisplatin and olaparib were selectively toxic to RPA-deficient breast cancer cells. Moreover, RPA expression is a crucial predictor of platinum response in EOC. Thus, a combined approach of RPA inhibition and PARP inhibition may offer a more effective treatment paradigm for ovarian cancer.35 0Item Restricted Assessing the Effectiveness of Educational Interventions on Breast Cancer Knowledge, Practice Uptake and Beliefs Among Adult Saudi Women: A Systematic Review(Saudi Digital Library, 2023-11-29) Sahli, Maryam; Hopkins, RuthBackground: Several systematic evaluations have examined the importance of educational interventions in promoting breast cancer screening (BCS) and reducing the incidence of breast cancer (BC). However, studies have yet to evaluate these educational interventions comprehensively among Saudi women. Aim: This review sought to systematically assess the efficacy of various educational interventions in enhancing women’s knowledge, breast self-examination (BSE) practices, and beliefs of breast cancer Screening (BCS) in different regions of the Kingdom of Saudi Arabia. Objectives: The research aimed to determine whether health education intervention programmes can increase the level of knowledge, BSE practice, and beliefs of BCS among women in Saudi Arabia and to identify the effective characteristics of these interventions in terms of the intervention’s duration, provider, strategies, theoretical framework and components (knowledge of BC, BSE uptake and health beliefs about BCS), and whether a one-component or multi-component approach is appropriate. Method: The study followed the Prospero protocol and utilised the Systematic Review guidelines and PICOSS inclusion and exclusion criteria. A comprehensive literature search used seven electronic databases: Scopus, Medline, CINHAL, EMBASA, Web of Science, ProQuest, and PsycInfo. In addition, a Google Scholar search and citation chaining from the included studies were conducted in June of 2023. Search terms were employed with AND and OR Boolean operators. Study type, intervention settings, country, region, intervention type and elements, sample size, age group, intervention duration, main finding, intervention effectiveness, data collection, delivery method, intervention sustainability, theoretical perspective (if applicable), and study limitations were described. Additionally, the Effective Public Health Practice Project (EPHPP) was used to evaluate the data quality of the included studies. The intervention strategies and study characteristics were analysed using a qualitative synthesis narrative of the included studies’ data. Results: Eleven interventional investigations were reviewed in their entirety. Multiple intervention strategies based on theory and language were primarily implemented among adult Saudi women in university and workplace contexts. The defining characteristics of the educational interventions included the provider, duration and mode of delivery. Conclusion: Most studies on the efficacy of educational interventions revealed favourable outcomes regarding Saudi women’s knowledge, BSE practice and beliefs of BCS. Thus, potential educational interventions could increase BSE practice, knowledge and ideas among Saudi women. Recommendations: The educational intervention studies included in this review had numerous limitations, including heterogeneous research designs, intervention strategies and outcome measures. Consequently, future research and policies implementing educational interventions for BC among Saudi women should consider these implications.24 0Item Restricted Understanding the Role of NIPBL loss on Drug Sensitivity in 3D Cancer Cell Line Cultures(Saudi Digital Library, 2023-10-23) Alotaibi, Aliyah; Peck, BarrieBreast cancer (BC) remains the most widespread cancer globally and stands as the fifth leading cause of mortality. Despite available therapeutic and preventive strategies for many BC subtypes, Triple-negative BC poses distinct challenges because of its high genomic instability and lack of conventional therapeutic biomarkers. This report offers a comprehensive overview of Triple-negative BC, emphasizing its unique attributes and genomic alterations. It further explores the present biomarkers aiding targeted therapies in Triple-negative BC, with a specific focus on the prospective role of NIPBL as a promising biomarker. The report subsequently presents the project’s scope, details its aims, objectives, methodologies, and materials used. More specifically, we find that loss of NIPBL in 3D cultures impacts vinka alkaloid sensitivity. Next, we investigated the expression of genes that encode known drug transporters and show that these are impacted by NIPBL loss and Vinorelbine treatment. In summary, we posit that NIPBL loss in cancer could represent as a negative prognostic biomarker for response to vinka alkaloids. 428 0