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Study finds key genes involved in aggressive form of breast cancer

6 June 2011
Appeared in BioNews 610

Scientists have identified a set of 15 genes that are associated with triple-negative breast cancer (TNBC), an aggressive form of the disease that does not respond to the drugs commonly used to treat other types of breast cancer.

TNBC accounts for a fifth of all breast cancer cases, and is more common in younger patients, African-American patients and patients with the BRCA1 gene mutation. Approximately 9,000 women are diagnosed with TNBC in Britain each year. Patients with TNBC have a poorer prognosis than women with other types of breast cancer, and have a higher rate of cancer recurrence.

TNBC tumours are known to contain many stem cell-like cells – rapidly-dividing and immature cells. They also lack the molecular receptors – oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) that are the normal targets of many breast cancer drugs. These drugs are consequently ineffective in TNBC patients.

In the new study, researchers at the Dana-Farber Cancer Institute, affiliated to Harvard Medical School in the US, aimed to identify genes associated with TNBC that could be used as new targets for drug development. By analysing patterns of gene activity in 587 TNBC breast cancer tissue samples from publicly-available datasets, the researchers were able to categorize TNBC tumours into six distinct subtypes based on their unique gene activity profiles.

They identified a set of 15 genes that are required for cell growth in TNBC tumours. These genes are associated with a cell 'signalling pathway' known as Jak2/Stat3. In laboratory tests, TNBC tumour cells were treated with drugs known to block the Jak2/Stat3 signalling pathway, and the researchers found that the drugs suppressed cell growth. The drugs were also effective in suppressing the growth of TNBC tumours in mice.

The research team believes these findings will have immediate clinical implications for TNBC patients. 'The discovery of these targets will rapidly lead to clinical trials with the hope of achieving one of the first specific therapies for triple-negative breast cancers', said Dr Kornelia Polyak, from the Dana-Farber Institute.

The Jak2/Stat3 signalling pathway is known to be involved in certain blood cancers. Two drugs that inhibit this signalling pathway are already in advanced clinical trials, with another three at earlier stages of drug development. The researchers are now beginning clinical trials for one of these drugs in TNBC patients, and estimate that up to 50-60 percent of TNBC patients have an 'abnormally activated' Jak2/Stat3 pathway that may be responsive to this drug treatment.

The researchers also hope to identify 'biomarkers' based on the gene activity profiles of the six TNBC subtypes that could be used to classify breast cancer tumours in patients, and indicate which targeted therapies are likely to be most effective for each person.

Dr Caitlin Palframan, policy manager at Breakthrough Breast Cancer, said: 'This research is very exciting as new treatments for triple-negative breast cancer are urgently needed. There are limited treatment options available for this group of patients so a targeted treatment would be a real breakthrough. However, this is early-stage research in mice and we look forward to seeing if this approach will prove effective in the upcoming clinical trials'. 

The study was published in the Journal of Clinical Investigation.

Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies
Journal of Clinical Investigation |  06/11
Overactive gene could provide key to treating one of deadliest breast cancers
Daily Mail |  2 June 2011
Triple-negative breast cancer: drug trial to start
Daily Telegraph |  2 June 2011
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