ARFGEF mutations: A mechanism for breast-to-brain metastasis

Cancer is one of the most devastating and major causes of death worldwide. In 2018, there were an estimated 18.1 million new cases and 9.6 million deaths globally. Most cancer-related fatalities, over 90%, are caused by the spread of cancer cells to other parts of the body, known as metastasis. Similarly, around 80% of deaths resulting from breast cancer are due to metastasis. Approximately 15-25% of breast tumours metastasise to the brain, and the outlook for patients with breast-to-brain metastasis is poor. Although it is established that mutations are responsible for driving metastasis, the specific gene alterations that promote brain metastasis remain unknown. Breast-to-brain metastasis occur when primary breast tumour cells disseminate to the brain, proliferating to form secondary tumours. Recent research has shown that metastatic brain cancer expresses neurotransmitter receptors and forms synaptic-like connections with neurons, contributing to tumour growth and survival. Exome sequencing of 26 breast-to-brain metastasis (BBM) cancers identified ARFGEF3 mutations in the BBM samples. This suggests that the absence of ARFGEF3 in breast cancer cells plays a role in the development of brain metastasis. The research presented here aims to uncover the molecular mechanisms underlying the metastatic process and identify potential therapeutic targets for preventing or treating brain metastasis in breast cancer patients. The knockout of ARFGEF3 by CRISPR Cas9 gene editing results in the regulation of several neurotransmitter receptors in a breast cancer cell line. The results presented here suggest a mechanism where mutations in ARFGEF3 may facilitate metastasis to and proliferation in the brain. Understanding this mechanism could facilitate the development of new therapeutic drugs targeting these pathways, potentially improving the treatment outcomes for metastatic breast cancer patients.

Name dc:type.qualificationname

MPhil

Grantor dc:publisher.institution

University of Wolverhampton

Year dc:date.issued

2025

Author dc:creator

• Allamsetty, Naga Harshitha

Advisor dc:contributor.advisor

• Morris, Mark

• breast cancer
• brain metastases
• BIG3 mutation
• neurotransmitter receptors
• synaptic complex
• pseudosynapses
• CRISPR
• Western Blot

Licence

• https://wlv.openrepository.com/bitstreams/f9a0c2a4-8531-494b-92a3-c253c0eaf3d6/download