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Beating breast cancer’s resistance to hormone treatments

Scientists uncovered a mechanism by which breast cancers can develop resistance to an important class of drugs called aromatase inhibitors used in the hormonal treatment of the disease.

The findings could be used to develop drugs that prevent breast cancers from building resistance to aromatase inhibitors, allowing more women to benefit from hormone therapy.

Aromatase inhibitors are an important part of hormone treatment for oestrogen receptor (ER)-positive breast cancer, which accounts for 70% of all newly diagnosed cases of breast cancer.

These tumours need oestrogen to survive and grow, so drugs called aromatase inhibitors, which can stop women’s bodies from producing oestrogen, are used in their treatment.

A study led by Professor Clare Isacke at The Institute of Cancer Research, London, discovered that the GDNF-RET signalling pathway in ER-positive breast cancer is linked to resistance to aromatase inhibitors in some cancers.

Her team found that breast cancer cells which have developed resistance to the drugs have higher levels of signalling by the GDNF-RET pathway than cells without resistance to aromatase inhibitors. ER receptors in the resistant cells were activated by GDNF-RET pathway signals, allowing tumours to grow even when treatment was blocking oestrogen production. But using a drug to block GDNF-RET signalling allowed these cells to become sensitive to treatment with aromatase inhibitors once again.

Breast cancer patients whose tumours had an activated GDNF-RET pathway were more likely to develop resistance to treatment with aromatase inhibitors than those whose pathway was not activated. They also had an increased risk of relapses and worse long- term chances of survival than patients whose tumours did not activate the GDNF-RET pathway.

Professor Isacke and her team hope the findings will help doctors to predict response to aromatase inhibitors and pick out who will benefit most from the treatment. Having discovered the importance of the GDNF-RET pathway in forming resistance to hormone therapy, the researchers believe that switching off this pathway in the clinic will increase the effectiveness of aromatase inhibitor treatment for women with breast cancer.

Morandi, A., Martin, LA., Gao, Q., Pancholi, S., Mackay, A., Robertson, D., Zvelebil, M., Dowsett, M., Plaza-Menacho, I. & Isacke, CM. (2013)GDNF-RET signaling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitorsCancer Research 73:3783-3795 doi: 10.1158/0008-5472.CAN-12-4265
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