Cathepsin D deficiency in mammary epithelium transiently stalls breast cancer by interference with mTORC1 signaling
Stephanie Ketterer, Julia Mitschke, Anett Ketscher, Manuel Schlimpert, Wilfried Reichardt, Natascha Baeuerle, Maria Elena Hess, Patrick Metzger, Melanie Boerries, Christoph Peters, Bernd Kammerer, Tilman Brummer, Florian Steinberg, Thomas Reinheckel
Abstract
Abstract Cathepsin D (CTSD) is a lysosomal protease and a marker of poor prognosis in breast cancer. However, the cells responsible for this association and the function of CTSD in cancer are still incompletely understood. By using a conditional CTSD knockout mouse crossed to the transgenic MMTV-PyMT breast cancer model we demonstrate that CTSD deficiency in the mammary epithelium, but not in myeloid cells, blocked tumor development in a cell-autonomous manner. We show that lack of CTSD impaired mechanistic Target of Rapamycin Complex 1 (mTORC1) signaling and induced reversible cellular quiescence. In line, CTSD-deficient tumors started to grow with a two-month delay and quiescent Ctsd -/- tumor cells re-started proliferation upon long-term culture. This was accompanied by rewiring of oncogenic gene expression and signaling pathways, while mTORC1 signaling remained permanently disabled in CTSD-deficient cells. Together, these studies reveal a tumor cell-autonomous effect of CTSD deficiency, and establish a pivotal role of this protease in the cellular response to oncogenic stimuli.