Investigating the role of CBFβ in breast cancer

Khan, Adiba Sanjana (2022) Investigating the role of CBFβ in breast cancer. PhD thesis, University of Glasgow.

Abstract

Despite the advances in therapy and improved patient mortality rates, breast cancer remains one of the leading causes of cancer associated deaths in women across the globe. The transcription co-factor, Core Binding Factor-beta (CBFβ), which is the binding partner for the RUNX family of proteins, is a recurrently mutated gene in breast cancer. Up to 14% of breast cancer patients harbour genetic alterations in this gene, across both oestrogen receptor (ER) positive and ER negative subtypes of the disease. The majority of these alterations have been found to be loss of function mutations and homozygous deletions in CBFβ, indicating a potential tumour suppressive role of this protein. The functionality of Cbfβ loss in mammary tumorigenesis was studied here using genetically engineered mouse models of a luminal B breast cancer model (MMTV-PyMT) and a Wnt/β-catenin driven mammary cancer mouse model. Consistent with loss of function mutations/deletions in patient cohorts, a tumour suppressor role of Cbfβ was confirmed for the first time in vivo where homozygous loss of Cbfβ in mammary epithelial cells dramatically accelerated Wnt/β-catenin driven tumour initiation and progression. Transcriptomic analysis of tumour samples deficient in Cbfβ revealed significant upregulation of genes encoding various activators of the Wnt/β-catenin pathway and downregulation of its inhibitors indicating marked augmentation of this signalling cascade. Genes involved in activation of other oncogenic pathways, including the Notch pathway, also appeared enriched in samples where Cbfβ was absent. Strikingly, alterations in the immune regulatory pathways of the Cbfβ-deficient tumour microenvironment were particularly evident in the RNAseq analysis and Cbfβ deficient pre-neoplastic glands also displayed an increased infiltration of immune cell infiltrates. Combined deletion of CBFβ binding partners, Runx1 and Runx2 showed a similar acceleration of Wnt/β-catenin driven tumorigenesis although differences in the transcriptomic and immune landscape between Runx1-Runx2 deficient and Cbfβ deficient tumours suggested that the mechanisms of action may not be entirely synonymous. Interestingly loss of Cbfβ from PyMT tumour cell lines showed that the tumour suppressor effect of CBFβ is not universal. This study provides the first in vivo evidence that Cbfβ loss might be associated with promotion of mammary tumorigenesis through hyperactivation of Wnt signalling and with an induction of a pro-tumorigenic immune response.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences > Beatson Institute of Cancer Research
• Supervisor's Name: Blyth, Professor Karen and Campbell, Dr. Kirsteen
• Date of Award: 2022
• Depositing User: Theses Team
• Unique ID: glathesis:2022-83317
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 20 Dec 2022 15:25
• Last Modified: 21 Dec 2022 14:46
• Thesis DOI: 10.5525/gla.thesis.83317
• URI: https://theses.gla.ac.uk/id/eprint/83317