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New research sheds light on treatment-resistant breast cancers


Wednesday 19 June 2013


Scientists have identified a new way of treating breast cancers that could overcome their resistance to a vitally important class of cancer drugs.

A team at The Institute of Cancer Research, London, has identified a mechanism used by breast cancers to become resistant to drugs called aromatase inhibitors, which form an important part of hormone treatment for the disease.

And the researchers found that blocking the resistance mechanism successfully restored cancer cells’ sensitivity to the drugs – opening the door to new strategies aimed at making existing treatments for breast cancer much more effective.

Around 50,000 new cases of breast cancer are diagnosed each year in the UK, with 70% classed as oestrogen receptor (ER)-positive. These tumours need oestrogen to survive and grow, so using drugs called aromatase inhibitors (AIs) which stop women’s bodies from producing oestrogen is the primary treatment for post-menopausal women. But some tumours can develop resistance to aromatase inhibitors, limiting the treatment choices available to doctors.  

The new study from The Institute of Cancer Research (ICR) was funded by the Association of International Cancer Research and Breakthrough Breast Cancer, with additional funding from the NIHR Biomedical Research Centre. The research shows that a signalling pathway in ER-positive breast cancer, known as GDNF-RET, is linked to AI resistance.

In breast cancer cell cultures resistant to AI treatment, the researchers found higher levels of signalling by the GDNF-RET pathway than in cultures without AI resistance. ER receptors in the AI resistant cells were activated by GDNF-RET pathway signals, allowing tumours to grow even when AIs were blocking oestrogen production, but using a drug to block GDNF-RET signalling allowed these cells to become sensitive to AI treatment again.

They found that breast cancer patients whose tumours had an activated GDNF-RET pathway were more likely to develop resistance to AI treatment, had an increased risk of relapses and worse long- term chances of survival than patients whose tumours did not activate the GDNF-RET pathway.

ICR researchers hope that the ability to predict response to AI therapy will help them identify the women who will benefit most from this treatment. Having discovered the importance of the GDNF-RET pathway in forming resistance to hormone therapy, the researchers believe they will be able to switch off this pathway in the clinic, thereby making AIs an effective treatment for more women with breast cancer.

Professor Clare Isacke, Professor of Molecular Cell Biology at The Institute of Cancer Research and Interim Director of the Breakthrough Breast Cancer Research Centre, said:

“Blocking oestrogen production with aromatase inhibitors is the treatment of choice for many women with breast cancer but some tumours can develop resistance to these drugs, making their cancers much harder to treat.

“Our work identifies an important signalling pathway involved in this resistance which can be used to predict whether women will respond to AI treatment. We hope this can be used by doctors to help decide whether AI treatment will be effective.

“We’ve shown that we can block the mechanism of resistance in ER-positive breast cancer cultures, and even reverse this effect in cells that no longer respond to AI treatment. We hope that in the future we can prevent breast cancers from developing resistance, allowing more women to benefit from treatments like hormone therapy that already available and have a proven track record.”

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