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Series GSE133328 Query DataSets for GSE133328
Status Public on Jun 30, 2020
Title Cathepsin D deficiency in mammary epithelium transiently stalls murine breast cancer by interference with mTORC1 signaling
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Cathepsin D (CTSD) is an aspartic protease mainly located within the endosomal/lysosomal compartment where it participates in intracellular protein breakdown. In breast cancer, CTSD is overexpressed and suggested as an independent marker of poor prognosis but the cells responsible for this association as well as the mode of action remain unclear. Here, we use a conditional CTSD knockout mouse, which allowed cell type-specific inactivation of CTSD in the transgenic MMTV-PyMT (PyMT) breast cancer model. We demonstrate that CTSD deficiency in mammary epithelial cells, but not myeloid cells, blocks tumor development in a cell-autonomous manner. By comparing CTSD-expressing with CTSD-deficient tumor cells from this model, we show that lack of CTSD induces cellular quiescence and disrupts mechanistic Target of Rapamycin Complex 1 (mTORC1) signaling under starvation. While quiescence is reversed under long-term starvation by rewiring oncogenic signaling pathways and gene expression, mTORC1 signaling remains permanently disabled in CTSD-deficient PyMT cells. Together, these studies reveal a tumor cell-autonomous effect of CTSD deficiency, and establish a pivotal role of this major aspartic protease in the cellular response to oncogenic stimuli.
Overall design RNA expression profiles were obtained of breast tumor tissue from 18-week-old control (CTSD wild type) and MMTV-cre;Ctsd-/- (CTSD-deficient) PyMT mice in 4 biological replicates each. RNA expression was also analyzed in spontaneously immortalized primary breast tumor cells obtained from one Ctsd+/+ (CTSD wild type) and one MMTV-cre;Ctsd-/- (Ctsd-/-) PyMT mouse. To this end, cells were grown in a mild starvation medium for short-term (10 days, ‘1% FCS’) or long-term (12 weeks, ‘1% FCS LT’) in 3 biological replicates each.
Contributor(s) Ketterer S, Reinheckel T, Hess ME, Metzger P, Boerries M
Citation(s) 33046706
Submission date Jun 26, 2019
Last update date Oct 27, 2020
Contact name Maria Elena Hess
Organization name Universitaetsklinikum Freiburg
Department Institute for Medical Bioinformatics and Systemsmedicine
Lab Boerries Lab
Street address Breisacherstr. 153
City Freiburg
ZIP/Postal code 79110
Country Germany
Platforms (2)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
GPL21493 Illumina HiSeq 3000 (Mus musculus)
Samples (20)
GSM3905804 WT rep1
GSM3905805 WT rep2
GSM3905806 WT rep3
BioProject PRJNA551126
SRA SRP212101

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Supplementary file Size Download File type/resource
GSE133328_RAW.tar 5.3 Mb (http)(custom) TAR (of TAB)
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Raw data are available in SRA
Processed data provided as supplementary file

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