Despite the improved treatment of breast cancer still about one third of women successfully treated for their primary tumor die from distant metastasis. Mechanisms underlying metastasis processes are still poorly understood. Essential cell biological steps in metastasis include migration, intravasation, homing, extravasation and survival/proliferation. In all these steps, there is a role for the so-called adhesome. The adhesome mediates the contact between cell and extracellular matrix (ECM) by integrin-dependent adhesions and it consists of several components like adaptor proteins, tyrosine kinases, and phosphatases. Also, numerous receptor protein tyrosine kinases including EGFR and ErbB2 are established prognostic markers for breast cancer progression.
In this project, we will use siRNA libraries directed against adhesome related genes, kinases and phosphatases. We will search for candidate genes which disturb cell motility parameters (e.g. random cell migration). This screen will be performed in highly invasive rat (MTLn3) and mouse (4T1) breast cancer cell line using a highthroughput platform. The most interesting genes resulting from this screen will be further studied in detail in in vitro assays including cell adhesion, 3D migration and focal adhesion dynamics using live cell imaging (confocal/TIRF). The final candidate genes will be validated in in vivo mouse breast cancer models, using Bioluminescence and intravital imaging which enables the visualization of migrating tumor cells and metastases.
Furthermore, a MEC transplantation model will be used to study the role of focal adhesion associated proteins and others in mammary gland development and the early steps in mammary tumorigenesis.
With these approaches we aim at identifying potential new targets for anti-cancer therapy.

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