1. Cathepsin D deficiency in mammary epithelium transiently stalls breast cancer by interference with mTORC1 signaling.
- Author
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Ketterer S, Mitschke J, Ketscher A, Schlimpert M, Reichardt W, Baeuerle N, Hess ME, Metzger P, Boerries M, Peters C, Kammerer B, Brummer T, Steinberg F, and Reinheckel T
- Subjects
- Animals, Breast Neoplasms genetics, Cathepsin D deficiency, Female, Humans, Mammary Glands, Animal metabolism, Mechanistic Target of Rapamycin Complex 1 genetics, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Signal Transduction, Breast Neoplasms metabolism, Cathepsin D genetics, Epithelium metabolism, Mechanistic Target of Rapamycin Complex 1 metabolism
- 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.- Published
- 2020
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