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 cells 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 Chapmans 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.
Weve 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.
Whats 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).
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Previously unknown genetic vulnerability in breast cancer cells target of research - India Education Diary
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