An investigation into the mechanisms of angiogenesis and breast cancer metastasis

Breast cancer survival rates have increased over the years due to early detection and therapeutic efficacy. However, after many years of what appears to be disease-free health, cancer can return in the form of a secondary metastatic tumour. Formation of new blood vessels is a crucial stage in the progression of primary tumours to metastatic tumours. In many cases primary breast tumours that metastasise to the brain occur. Brain tumours are heterogenous malignancies with a low survival rate. Tumours often development therapy resistance by secreting different pro-angiogenic growth factors that allow them to overcome the effect of anti-angiogenic drugs. Thus, characterising the mechanisms that promote tumour angiogenesis may help to stop the development of tumour metastasis. Here it was determined that ATF2 is a downstream molecule activated (phosphorylated) by major pro-angiogenic factors and that its suppression in HUVECs resulted in increased upregulation of Notch signalling pathway (major regulator of angiogenesis) ligand DLL1 and DLL4. Additionally, we investigated genomic changes that may be involved in the development and progression of breast to brain metastasis (BBM). Whole exome sequencing (WES) of 26 breast to brain metastases was carried out. Bioinformatic analysis of WES data identified recurrent genomic alterations in several genes that may be associated with BBM development including an ARFEFG protein family member gene, BIG3. Functional analysis of BIG3 showed that this gene is involved in the regulation of neurotransmitter receptors subunits in the BIG3-knockout MCF-7 breast cancer cell line. Neurotransmitter regulation has been shown as one mechanism through which brain tumours integrate into the neuronal signalling network to promote colonisation of the brain. Results presented here show that investigating the possible mechanisms behind tumour angiogenesis, and the molecular changes that may be involved in metastatic tumour development and brain colonisation offers a better understanding of tumour mechanisms for growth and survival which can offer an opportunity for the development of new therapeutic targets.

Name dc:type.qualificationname

PhD

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Wolverhampton

Year dc:date.issued

2023

Author dc:creator

• Olivares, Ivonne

Advisor dc:contributor.advisor

• Morris, Mark

• angiogenesis regulations
• endothelial cells
• ATF2
• breast to brain metastasis
• CRISPR_Cas9
• gene editing

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 International

Licence

• https://wlv.dspace7.openrepository.com/bitstreams/e4d17653-850c-44c9-bb6f-cba792d3a249/download