title: Preclinical efficacy of cystatin C to target the oncogenic activity of transforming growth factor Beta in breast cancer.
abstract: We previously identified cystatin C (CystC) as a novel antagonist of transforming growth factor beta (TGF-beta) signaling in normal and malignant cells. However, whether the anti-TGF-beta activities of CystC can be translated to preclinical animal models of breast cancer growth and metastasis remains unproven. Assessing the preclinical efficacy of CystC was accomplished using metastatic 4T1 breast cancer cells, whose oncogenic responses to TGF-beta were inhibited both in vitro and in vivo. Indeed, we observed CystC to prevent TGF-beta from stimulating the growth and pulmonary metastasis of 4T1 tumors in mice in part by reducing the extent of Smad2, p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase 1/2 phosphorylation present in 4T1 tumors. We also found CystC to significantly antagonize angiogenesis in developing 4T1 tumors, suggesting a novel role for CystC in uncoupling TGF-beta signaling in endothelial cells (ECs). Accordingly, CystC dramatically reduced murine and human EC responsiveness to TGF-beta, including their ability to regulate the expression of 1) TGF-beta signaling components, 2) inhibitor of differentiation (ID) family members, and 3) matrix metalloproteinases and their inhibitors (TIMPs) and to undergo cell invasion and angiogenic sprouting stimulated by TGF-beta. Importantly, CystC prevented TGF-beta from stimulating vessel development in Matrigel plugs implanted into genetically normal mice. Collectively, our findings provide the first preclinical evidence that CystC is efficacious in preventing breast cancer progression and angiogenesis stimulated by the oncogenic TGF-beta signaling system and suggest that CystC-based chemotherapeutics possesses translational efficacy to one day treat and improve the clinical course of late-stage breast cancers.
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Maozhen
authors.initials: M
authors.lastname: Tian
authors.forename: William P
authors.initials: WP
authors.lastname: Schiemann
references.citation: Lancet Oncol. 2004 Apr;5(4):229-39
references.pmid: 15050954
references.citation: Microvasc Res. 2006 Jan;71(1):12-9
references.pmid: 16405919
references.citation: Nat Rev Cancer. 2006 Oct;6(10):764-75
references.pmid: 16990854
references.citation: Cancer Res. 2008 Mar 1;68(5):1462-70
references.pmid: 18316610
references.citation: Chest. 2005 Dec;128(6 Suppl):585S-590S
references.pmid: 16373850
references.citation: Blood. 2002 Dec 15;100(13):4495-501
references.pmid: 12453878
references.citation: Nature. 1999 Oct 14;401(6754):670-7
references.pmid: 10537105
references.citation: DNA Cell Biol. 2004 Jun;23(6):367-79
references.pmid: 15231070
references.citation: Protein Sci. 1997 Jan;6(1):5-12
references.pmid: 9007972
references.citation: Mol Cancer Res. 2004 Mar;2(3):183-95
references.pmid: 15037657
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19506-11
references.pmid: 18048329
references.citation: Nat Rev Cancer. 2005 Aug;5(8):603-14
references.pmid: 16034366
references.citation: Science. 2006 Sep 22;313(5794):1785-7
references.pmid: 16990548
references.citation: Future Oncol. 2006 Dec;2(6):743-63
references.pmid: 17155901
references.citation: Nat Rev Mol Cell Biol. 2007 Nov;8(11):857-69
references.pmid: 17895899
references.citation: Cancer Res. 2007 Apr 15;67(8):3752-8
references.pmid: 17440088
references.citation: J Biol Chem. 2002 May 31;277(22):19991-7
references.pmid: 11901155
references.citation: Blood. 2008 Jan 15;111(2):633-42
references.pmid: 17911384
references.citation: Mol Cell. 2008 Feb 1;29(2):157-68
references.pmid: 18243111
references.citation: Cancer Cell. 2008 Jan;13(1):23-35
references.pmid: 18167337
references.citation: Oncogene. 2004 Mar 18;23(12):2224-30
references.pmid: 14730346
references.citation: Cancer Cell. 2004 May;5(5):443-53
references.pmid: 15144952
references.citation: Cell Cycle. 2004 Dec;3(12):1516-619
references.pmid: 15539953
references.citation: Nat Rev Cancer. 2003 Nov;3(11):807-21
references.pmid: 14557817
references.citation: Differentiation. 2002 Dec;70(9-10):574-82
references.pmid: 12492498
references.citation: Lab Invest. 1996 Mar;74(3):600-8
references.pmid: 8600310
references.citation: Ann N Y Acad Sci. 2006 Nov;1089:119-26
references.pmid: 17261761
references.citation: Nat Med. 2003 Apr;9(4):407-15
references.pmid: 12652295
references.citation: Nat Rev Cancer. 2006 Jul;6(7):506-20
references.pmid: 16794634
references.citation: Mol Cell Biol. 2004 May;24(10):4241-54
references.pmid: 15121845
references.citation: Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4315-30
references.pmid: 16857807
references.citation: Am J Pathol. 2003 Feb;162(2):533-46
references.pmid: 12547711
references.citation: EMBO J. 2002 Apr 2;21(7):1743-53
references.pmid: 11927558
references.citation: Int J Cancer. 2007 Nov 15;121(10):2119-24
references.pmid: 17849476
references.citation: J Cell Physiol. 2002 Dec;193(3):299-318
references.pmid: 12384983
references.citation: Trends Cardiovasc Med. 2003 Oct;13(7):301-7
references.pmid: 14522471
references.citation: Nat Rev Drug Discov. 2004 Dec;3(12):1011-22
references.pmid: 15573100
references.citation: J Biol Chem. 1996 May 31;271(22):12755-61
references.pmid: 8662721
references.citation: Cancer Res. 2008 May 15;68(10):3835-43
references.pmid: 18483268
references.citation: Cytokine Growth Factor Rev. 1997 Mar;8(1):21-43
references.pmid: 9174661
references.citation: Expert Rev Anticancer Ther. 2007 May;7(5):609-11
references.pmid: 17492924
references.citation: Lab Invest. 2006 Feb;86(2):116-29
references.pmid: 16344855
references.citation: Carcinogenesis. 2008 Feb;29(2):244-51
references.pmid: 18174260
references.citation: Exp Cell Res. 1993 Feb;204(2):356-63
references.pmid: 7679998
references.citation: Mol Cell. 2003 Apr;11(4):915-26
references.pmid: 12718878
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2626-31
references.pmid: 10716993
references.citation: Mol Cell. 2003 Oct;12(4):817-28
references.pmid: 14580334
references.citation: Nature. 2000 Sep 14;407(6801):249-57
references.pmid: 11001068
references.citation: Cell Mol Life Sci. 2002 Sep;59(9):1503-12
references.pmid: 12440772
references.citation: Curr Opin Investig Drugs. 2006 Jun;7(6):513-21
references.pmid: 16784021
references.citation: Oncogene. 2004 Jun 10;23(27):4681-9
references.pmid: 15122332
references.citation: Cardiovasc Res. 2005 Feb 15;65(3):599-608
references.pmid: 15664386
references.citation: Breast Cancer Res. 2005;7(5):R844-53
references.pmid: 16168131
references.citation: Cancer Res. 2006 Mar 1;66(5):2621-9
references.pmid: 16510581
references.citation: Nat Med. 2003 Jun;9(6):653-60
references.pmid: 12778163