Cathepsin D deficiency in mammary epithelium transiently stalls breast cancer by interference with mTORC1 signaling

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.

Prognostic significance and oncogene function of cathepsin A in hepatocellular carcinoma

“…Previous studies have found that the overexpression of cathepsin B leads to the invasiveness and metastasis of breast cancer, pancreatic cancer, HCC, and colorectal cancer, by activating the ErbB oncogenic signaling pathway 11 – 14 . The cytosol concentration of cathepsin D was found to have a strong influence on metastasis in breast cancer 15 , 16 . In addition, cathepsin K was found to have a high correlation with the progression of prostate cancer and breast cancer 17 , 18 .…”

A 9-kDa matricellular SPARC fragment released by cathepsin D exhibits pro-tumor activity in the triple-negative breast cancer microenvironment

“…Cells were stained with 0.1% crystal violet, and absorbance was measured at 570 nm. APQQEALPDE [18][19][20][21][22][23][24][25][26][27] Glu-C 0.98 (2) APQQEALPDETE [18][19][20][21][22][23][24][25][26][27][28][29] Glu-C 0.88 (13) APQQEALPDETEVVE [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] Glu-C 1.12 (6) APQQEALPDETEVVEE [18][19][20][21][22][23][24][25][26][27][28][29][30]…”

“…Purified 52-kDa cath-D auto-activates in acidic conditions, giving rise to a catalytically active 51-kDa pseudocath-D form that retains the 18 residues (27-44) of the pro-segment [14]. Cath-D affects the tumor and its microenvironment by increasing BC cell proliferation [13,[15][16][17][18], and by stimulating mammary fibroblast outgrowth [19,20], angiogenesis [15,21], and metastasis formation [17]. However, little is known about the molecular mechanisms and the substrates involved in these processes.…”

Peran Cathepsin D Inhibitor Pada Terapi Kanker

“…Cathepsin D dianggap sebagai penanda prognosis independen pada jenis kanker dan peningkatan Cathepsin D berhubungan dengan meningkatnya keganasan dari kanker termasuk kanker payudara, kanker ovarium, kanker lambung dan kanker prostat. Hal ini tentu saja mendasari bahwa Cathepsin D merupakan target potensial untuk mengobati kanker (Ketterer et al, 2020;Xu et al, 2017).…”