Role of splice- and translation-variants of the cysteine protease cathepsin L in the progression and metastasis of mammary cancer

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Proteolytic enzymes are versatile players in the growth and dissemination of malignant tumors. We have recently shown that overexpression of cathepsin L promotes formation of lung metastasis in the MMTV-PyMT mouse model for metastasizing breast cancer. In addition we established that cathepsin L biosynthesis is maintained at high level even under tumor-relevant stress conditions. In the future we want to elucidate the intracellular tumor promoting functions of cathepsin L. Of special interest is the possible link of the lysosomal protease to a central ceck point of cell growth, i.e. the mTOR pathway. Thus, this project aims to elucidate how the lysosomal protease cathepsin L affects tumor growth and metastasis by analysis of breast cancers in mouse models and human breast cancer cell lines. As preparatory work we generated a transgenic mouse allowing for selective ablation of cathepsin L in various cell types residing in the cancer. This mouse line has been crossed to the MMTV-PyMT mouse model of metastasizing breast cancer and tumor progression and metastatic dissemination will be systematically studied. Functional analysis of primary and immortalized cell cultures derived from the mouse models and expression studies in primary breast cancer specimens of patients complement the genetic animal studies.The following key questions will be addressed: 1) Cell type selective ablation of cathepsin L in the cancer cells of the MMTV-PyMT breast cancer model 2) mTOR activity, lysosomal biogenesis and autophagy will be studied upon cathepsin inhibition in tumor-relevant cell culture conditions. 3) Biochemical analysis of purified cathepsin L-deficient lysosomes. 4) Functional validation of the novel molecular links in vivo.