Microenvironmental ADAM17 as key regulator of breast cancer

Breast cancer is by far the most frequently diagnosed type of tumour in women and also has the highest mortality rate. A reduced or even absent expression of sex hormone receptors still results in a moderate to poor prognosis in breast cancer. A more detailed understanding of the tumour microenvironment in breast cancer is therefore key to develop new therapeutic avenues in breast cancer. Depending on the tumour microenvironment, exhausted T lymphocytes with strong expression of immune checkpoint molecules such as PD1 are found in breast tumours. However, immune checkpoint inhibitors such as anti-PD1 antibodies have only limited efficacy in breast cancer. A disintegrin and metalloprotease (ADAM) 17 acts as molecular scissors that can cut proteins off the cell surface. ADAM17 can thus regulate a large number of intercellular signalling processes. However, this regulation has not yet been systematically characterised. ADAM17 is expressed in the tumour microenvironment of breast cancer and correlates with the exhaustion of tumour-directed T lymphocytes. In previous projects, we demonstrated that the expression of ADAM17 in blood vessel cells promotes the metastasis of lung and skin tumours. In the project ADAM17 in the microenvironment as a regulator of breast cancer we will investigate the role of ADAM17 in cells of the blood vessels, T lymphocytes, dendritic cells and macrophages. Using appropriate breast cancer mouse models, we will investigate how ADAM17 and ADAM17- regulated signalling pathways prevent an efficient tumour-targeted immune response. We will also analyse how ADAM17 in blood vessel cells influences breast cancer metastasis. In collaboration with clinical breast cancer specialists from Salzburg, Jena and Kiel, we will examine surgically removed tissue from breast cancer patients using state-of-the-art histological methods and investigate which ADAM17-mediated signalling pathways influence the clinical course of breast cancer. We will also experimentally address whether precise pharmacological inhibition of ADAM17 represents a new therapeutic option for breast cancer. Through our project, we hope to gain valuable insights into the molecular mechanisms by which breast tumours can evade the body`s immune response. We hope to be able to contribute to the development of new therapeutic strategies for the efficient treatment of breast cancer.