Oxford University researchers discover 'genetic vulnerability' in breast cancer cells

September 09, 2020

The study, published in the scientific journal Nature, has uncovered a genetic vulnerability present in nearly 10% percent of all breast cancers tumours, and found a way to target this vulnerability and selectively kill cancer cells. Each year, over five thousand newly diagnosed cases of breast cancer in the UK alone will carry this particular genetic fault, a proportion roughly double that driven by hereditary mutations such as those in the well-known BRCA genes.

A University of Oxford team of scientists led by Professor Ross Chapman, working together with researchers working at the Johns Hopkins University School of Medicine in Baltimore, USA, discovered that cells originating from a specific subset of human breast cancer tumours, could be killed with a chemical that inhibits PLK4, an enzyme important for a specialized part of a cell called the centrosome. A cell's centrosomes performs important functions during cell division, where it regulates the process in which copies of each chromosome are accurately segregated between two identical daughter cells. Normally, cells have safety mechanisms that protect them from losing their centrosomes. But the researchers discovered that these breast cancer cells could not survive without centrosomes.

The Oxford team wondered if the cancer cells they were studying had a genetic change that made them especially reliant on their centrosomes, and turned their attention to one feature of these cancer cells, an abnormal repeated stretch of a particular segment on chromosome 17. This genetic abnormality, known as 17q23 amplification, is already familiar to cancer researchers given its very high incidence in breast cancer.

Peter Yeow, a graduate student in Dr Chapman's laboratory, performed experiments that then revealed a gene known as TRIM37 was much more active in cells that had 17q23 amplification. They then went on to show overactive TRIM37 resulted in faulty centrosomes, which in turn led to mistakes during cell division. They speculate that the 'daughter' cells born of these abnormal cell divisions are much more likely to acquire new genetic mutations.

'We think that what is happening is that if cells acquire too many copies of TRIM37, the normally very carefully orchestrated process of cell division goes haywire, which in turn leads to our genomes becoming unstable" says Professor Chapman, from the MRC Weatherall Institute of Molecular Medicine at Oxford University. "This kind of genomic instability, where cells acquire all sorts of alterations to their genomes as they divide, is one of the hallmarks of cancer development.'

This means that cells with the 17q23 amplification are more likely to become cancerous. However, the researchers revealed this characteristic of cancer comes at a cost, the exact same defect leaves the cells entirely reliant on their centrosomes for cell division, a process central to tumour development. The researchers then demonstrated this weakness could be exploited using a drug that targets PLK4 and causes cells to lose their centrosomes, and that this treatment killed cancer cells with 17q23 amplification.

'It is slightly ironic that the same thing that makes the cells more likely to become cancerous also makes them uniquely vulnerable to losing their centrosomes, but is useful to us as scientists, because it means that we may be able to selectively target this kind of cancer cell in patients without affecting their healthy cells,' says Professor Chapman.

Unfortunately, the chemical PLK4 inhibitor that the researchers used to deplete centrosomes in cancer cells is not suitable for use in patients. However, they hope this information can be used to search for new PLK4-targeting drugs that have the same effect.

'We've found a previously unknown genetic vulnerability in breast cancer, and discovered a means to exploit this vulnerability and selectively kill cancer cells,' says Dr Chapman. 'We now hope that other researchers and pharmaceutical companies can generate new drugs that can target this process, to produce more effective and safer cancer treatments.'

What's also promising is that this genetic fault has also been detected in other cancer types, apart from breast cancer. 'Virtually any tumour, irrespective of origin, could be targeted if it harbours the 17q23 amplification. This greatly expands the number of patients that stand to benefit from therapies that may emerge from our study,' says Yeow.
Dr. J. Ross Chapman is a Cancer Research UK Career Development Fellow and Lister Institute Research Prize Fellow. The work was funded predominantly through grants from Cancer Research UK and the National Institutes of Health (USA).

University of Oxford

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.