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Human breast cancer tissue stained for Ret (red).




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FMI

July 19, 2013

Molecular validation of novel breast cancer therapeutic target

Under the leadership of Nancy Hynes, scientists from the Friedrich Miescher Institute for Biomedical Research have identified a potential novel target for breast cancer treatment. The scientists could show that breast cancer patients with high levels of the receptor tyrosine kinase Ret have a worse prognosis; and that blocking Ret not only decreases tumor growth but also impacts the potential of the cancer to spread throughout the body.

In recent years, there have been many advances in breast cancer treatment that bring hope to patients. However, breast cancer prognosis is still linked strongly to the type of cancer the patient suffers from. For several breast cancer subtypes powerful therapies exist: hormonal therapies help control tumors that are estrogen or progesterone receptor positive, antibodies against the receptor tyrosine kinase HER2 prolong survival of patients with the HER2 positive subtype. However, between 10-17% of breast cancers, so-called “triple negative” breast cancers, do not express estrogen receptor or HER2 and are not eligible for either therapy. Moreover, most initially treatable breast cancer patients develop resistance and often relapse with metastatic disease. It is therefore important to identify novel targets and inhibitors that could be useful in breast cancer therapy.

Nancy Hynes, group leader at the Friedrich Miescher Institute for Biomedical Research and Professor at the University of Basel, and her team have now identified a potential novel target in breast cancer. Their findings, which are published today in EMBO Molecular Medicine, show that elevated levels of the receptor tyrosine kinase Ret are associated with a lower likelihood of long-term survival.

In their study the researchers examined tumor tissue microarrays of approximately 100 breast cancer patients who had surgically removed their primary tumor and correlated the levels of Ret in the sample with long-term metastasis-free survival. They found that Ret receptor levels were elevated in different sub-types of breast cancer, and elevated Ret levels correlated with decreased survival. To study Ret’s role in breast cancer they used different breast cancer models and could show that Ret receptor activation stimulated migration of breast tumor cell lines and also “rescued” them from the anti-proliferative effects of hormonal therapies. In other experiments, the breast cancer models were grown as tumors in mice to study the effects of Ret inhibitors on the progress and spread of the cancer. “Initial experiments in tumor-bearing mice, which serve as model organisms for the study of breast cancer, have revealed that Ret selective inhibitors significantly block the spread of cancer and decrease the number of metastatic tumors found in the lungs,” explained Hynes.

In other experiments, four different cancer cell lines were used and injected into mice to study the effects of Ret inhibitors on the progress and spread of the cancer. “Initial experiments in mice that serve as model organisms for the study of breast cancer have revealed that specific inhibitors significantly block the spread of cancer and decrease the number of metastatic tumors found in the lungs,” explained Hynes.

These findings suggest that Ret kinase might be an attractive and novel alternative therapeutic target in selected groups of breast cancer patients. “Our findings demonstrate that blocking Ret kinase not only decreases the growth of tumors but also impacts the potential of the cancer to spread throughout the body,” Hynes said.

With material from the press release of EMBO Molecular Medicine

Original publication
Gattelli A, Nalvarte I, Boulay A, Roloff TC, Schreiber M, Carragher N, Macleod KK, Schlederer M, Lienhard S, Kenner L, Torres-Arzayus MI, Hynes NE (2013) Ret inhibition decreases growth and metastatic potential of estrogen re-ceptor positive breast cancer cells. EMBO Mol Med, 2013 Jul 19. doi: 10.1002/emmm.201302625. [Epub ahead of print]

On Nancy Hynes
Nancy Hynes is a senior group leader at the FMI and professor at the University of Basel. She is interested in the molecular basis of breast cancer. She and her group study how extracellular signals are interpreted within a cell and how misinterpretation of these signals can lead to malignant growth. In particular, she is interested in the receptors of the tyrosine kinase family and how their aberrant expression contributes to breast cancer.
» More about Nancy Hynes

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