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The Ret Receptor Tyrosine Kinase Pathway Functionally Interacts with the ER Pathway in Breast Cancer

¹ Friedrich Miescher Institute for BioMedical Research; and ² Novartis Institute for BioMedical Research, Oncology, Basel, Switzerland; ³ Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland; and ⁴ University Hospital, Lausanne, Switzerland

Requests for reprints: Heidi A. Lane, Novartis Institute for BioMedical Research, Oncology, Basel, Switzerland and Nancy E. Hynes, Friedrich Miescher Institute for BioMedical Research, Basel, Switzerland.

Key Words: glial-derived neurotrophic factor signaling • human breast cancer • anchorage-independent growth • endocrine signaling

A limited number of receptor tyrosine kinases (e.g., ErbB and fibroblast growth factor receptor families) have been genetically linked to breast cancer development. Here, we investigated the contribution of the Ret receptor tyrosine kinase to breast tumor biology. Ret was expressed in primary breast tumors and cell lines. In estrogen receptor (ER)-positive MCF7 and T47D lines, the ligand (glial-derived neurotrophic factor) activated signaling pathways and increased anchorage-independent proliferation in a Ret-dependent manner, showing that Ret signaling is functional in breast tumor cells. Ret expression was induced by estrogens and Ret signaling enhanced estrogen-driven proliferation, highlighting the functional interaction of Ret and ER pathways. Furthermore, Ret was detected in primary cancers, and there were higher Ret levels in ER-positive tumors. In summary, we showed that Ret is a novel proliferative pathway interacting with ER signaling in vitro. Expression of Ret in primary breast tumors suggests that Ret might be a novel therapeutic target in breast cancer. [Cancer Res 2008;68(10):3743–51]