Research Papers:

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

Janja Završnik, Miha Butinar, Mojca Trstenjak Prebanda, Aleksander Krajnc, Robert Vidmar, Marko Fonović, Anders Grubb, Vito Turk, Boris Turk and Olga Vasiljeva _

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Oncotarget. 2017; 8:73793-73809. https://doi.org/10.18632/oncotarget.17379

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Janja Završnik1,2, Miha Butinar1, Mojca Trstenjak Prebanda1, Aleksander Krajnc1,2, Robert Vidmar1,2, Marko Fonović1,4, Anders Grubb3, Vito Turk1,2, Boris Turk1,4,5 and Olga Vasiljeva1,6

1Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute, SI-1000 Ljubljana, Slovenia

2Jozef Stefan International Postgraduate School, Sl-1000 Ljubljana, Slovenia

3Department of Clinical Chemistry, Laboratory Medicine, University Hospital, SE-22185 Lund, Sweden

4Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, SI-1000 Ljubljana, Slovenia

5Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia

6Current address: CytomX Therapeutics, Inc., South San Francisco, CA 94080, USA

Correspondence to:

Olga Vasiljeva, email: olga.vasiljeva@gmail.com

Keywords: cathepsin inhibitor, cystatin C, breast cancer, mouse model

Received: December 09, 2016    Accepted: March 22, 2017    Published: April 24, 2017


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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