Breast cancer is the second leading cause of cancer death in women after lung cancer. Breast cancers are frequently associated with bone metastasis resulting in severe disease burden pain, and death. Josef Penninger was the first to show that the Receptor-activator of NF-kB(RANK) and its ligand (RANKL) are essential for osteoclast differentiation, activation and survival, as well as for mammary gland development. In addition, expression of RANK was detected in various breast cancer cell lines. Stimulation of RAN KL via RANK directly triggers chemotactic migration of epithelial breast cancer, prostate cancer, and melanoma cellsRANKL further causes chemotaxis of primary mammary epithelial cells and osteoclasts.
Our hypothesis is therefore that, RANK/RANKL play an important role in breast cancer and the inhibition of RANK/RANKL might be useful to abrogate metastasis of epithelial tumours to the bones. To better understand the molecular and cellular aspects of mammary tumours and metastasis as well as to test and develop new therapies we will analyse the complex role ofRANK/RANKL in breast cancer formation by crossing our existing RANK and RANKL knock-out mice into various transgenic mouse lines that develop breast cancers. A cell culture system will be established to study the molecular signalling cascades of RANK and RANKL, involved in cell migration and metastasis. Additionally, using a new tetraploid-G4 mouse ES celsystem we will set up a platform for the rapid generation of novel mouse models for breast cancer studies. The long-term goal is to contribute to the finding of additional methods and drugs to cure breast cancer.
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