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Cystatin C deficiency suppresses tumor growth in a breast cancer model through decreased proliferation of tumor cells

Završnik, Janja; Butinar, Miha; Prebanda, Mojca Trstenjak; Krajnc, Aleksander; Vidmar, Robert; Fonović, Marko; Grubb, Anders LU ; Turk, Vito; Turk, Boris and Vasiljeva, Olga (2017) In Oncotarget 8(43). p.73793-73809
Abstract

Cysteine cathepsins are proteases that, in addition to their important physiological functions, have been associated with multiple pathologies, including cancer. Cystatin C (CstC) is a major endogenous inhibitor that regulates the extracellular activity of cysteine cathepsins. We investigated the role of cystatin C in mammary cancer using CstC knockout mice and a mouse model of breast cancer induced by expression of the polyoma middle T oncoprotein (PyMT) in the mammary epithelium. We showed that the ablation of CstC reduced the rate of mammary tumor growth. Notably, a decrease in the proliferation of CstC knockout PyMT tumor cells was demonstrated ex vivo and in vitro, indicating a role for this protease inhibitor in signaling pathways... (More)

Cysteine cathepsins are proteases that, in addition to their important physiological functions, have been associated with multiple pathologies, including cancer. Cystatin C (CstC) is a major endogenous inhibitor that regulates the extracellular activity of cysteine cathepsins. We investigated the role of cystatin C in mammary cancer using CstC knockout mice and a mouse model of breast cancer induced by expression of the polyoma middle T oncoprotein (PyMT) in the mammary epithelium. We showed that the ablation of CstC reduced the rate of mammary tumor growth. Notably, a decrease in the proliferation of CstC knockout PyMT tumor cells was demonstrated ex vivo and in vitro, indicating a role for this protease inhibitor in signaling pathways that control cell proliferation. An increase in phosphorylated p-38 was observed in CstC knockout tumors, suggesting a novel function for cystatin C in cancer development, independent of the TGF-β pathway. Moreover, proteomic analysis of the CstC wild-type and knockout PyMT primary cell secretomes revealed a decrease in the levels of 14-3-3 proteins in the secretome of knock-out cells, suggesting a novel link between cysteine cathepsins, cystatin C and 14-3-3 proteins in tumorigenesis, calling for further investigations.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Breast cancer, Cathepsin inhibitor, Cystatin C, Mouse model
in
Oncotarget
volume
8
issue
43
pages
17 pages
publisher
Impact Journals, LLC
external identifiers
  • scopus:85030103088
  • wos:000411760400038
ISSN
1949-2553
DOI
10.18632/oncotarget.17379
language
English
LU publication?
yes
id
072870b5-61d5-445c-8d37-bd5759db0a7c
date added to LUP
2017-11-07 15:35:43
date last changed
2018-04-29 04:43:37
@article{072870b5-61d5-445c-8d37-bd5759db0a7c,
  abstract     = {<p>Cysteine cathepsins are proteases that, in addition to their important physiological functions, have been associated with multiple pathologies, including cancer. Cystatin C (CstC) is a major endogenous inhibitor that regulates the extracellular activity of cysteine cathepsins. We investigated the role of cystatin C in mammary cancer using CstC knockout mice and a mouse model of breast cancer induced by expression of the polyoma middle T oncoprotein (PyMT) in the mammary epithelium. We showed that the ablation of CstC reduced the rate of mammary tumor growth. Notably, a decrease in the proliferation of CstC knockout PyMT tumor cells was demonstrated ex vivo and in vitro, indicating a role for this protease inhibitor in signaling pathways that control cell proliferation. An increase in phosphorylated p-38 was observed in CstC knockout tumors, suggesting a novel function for cystatin C in cancer development, independent of the TGF-β pathway. Moreover, proteomic analysis of the CstC wild-type and knockout PyMT primary cell secretomes revealed a decrease in the levels of 14-3-3 proteins in the secretome of knock-out cells, suggesting a novel link between cysteine cathepsins, cystatin C and 14-3-3 proteins in tumorigenesis, calling for further investigations.</p>},
  author       = {Završnik, Janja and Butinar, Miha and Prebanda, Mojca Trstenjak and Krajnc, Aleksander and Vidmar, Robert and Fonović, Marko and Grubb, Anders and Turk, Vito and Turk, Boris and Vasiljeva, Olga},
  issn         = {1949-2553},
  keyword      = {Breast cancer,Cathepsin inhibitor,Cystatin C,Mouse model},
  language     = {eng},
  number       = {43},
  pages        = {73793--73809},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {Cystatin C deficiency suppresses tumor growth in a breast cancer model through decreased proliferation of tumor cells},
  url          = {http://dx.doi.org/10.18632/oncotarget.17379},
  volume       = {8},
  year         = {2017},
}