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Breast Cancer Research
Published in: Breast Cancer Research 6/2005

Open Access 01-12-2005 | Research article

Inhibition of CCN6 (WISP3) expression promotes neoplastic progression and enhances the effects of insulin-like growth factor-1 on breast epithelial cells

Authors: Yanhong Zhang, Quintin Pan, Hui Zhong, Sofia D Merajver, Celina G Kleer

Published in: Breast Cancer Research | Issue 6/2005

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Abstract

Introduction

CCN6/WISP3 belongs to the CCN (Cyr61, CTGF, Nov) family of genes that contains a conserved insulin-like growth factor (IGF) binding protein motif. CCN6 is a secreted protein lost in 80% of the aggressive inflammatory breast cancers, and can decrease mammary tumor growth in vitro and in vivo. We hypothesized that inhibition of CCN6 might result in the loss of a growth regulatory function that protects mammary epithelial cells from the tumorigenic effects of growth factors, particularly IGF-1.

Method

We treated human mammary epithelial (HME) cells with a CCN6 hairpin short interfering RNA.

Results

CCN6-deficient cells showed increased motility and invasiveness, and developed features of epithelial-mesenchymal transition (EMT). Inhibition of CCN6 expression promoted anchorage-independent growth of HME cells and rendered them more responsive to the growth effects of IGF-1, which was coupled with the increased phosphorylation of IGF-1 receptor and insulin receptor substrate-1 (IRS-1).

Conclusion

Specific stable inhibition of CCN6 expression in HME cells induces EMT, promotes anchorage-independent growth, motility and invasiveness, and sensitizes mammary epithelial cells to the growth effects of IGF-1.
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Literature
1.
Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Furga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV, et al: Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet. 1999, 23: 94-98. 10.1038/12699.CrossRefPubMed
2.
Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, Brush J, Taneyhill LA, Deuel B, Lew M, et al: WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc Natl Acad Sci USA. 1998, 95: 14717-14722. 10.1073/pnas.95.25.14717.CrossRefPubMedPubMedCentral
3.
Perbal B: NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues. Mol Pathol. 2001, 54: 57-79. 10.1136/mp.54.2.57.CrossRefPubMedPubMedCentral
4.
Thorstensen L, Holm R, Lothe RA, Trope C, Carvalho B, Sobrinho-Simoes M, Seruca R: WNT-inducible signaling pathway protein 3, WISP-3, is mutated in microsatellite unstable gastrointestinal carcinomas but not in endometrial carcinomas. Gastroenterology. 2003, 124: 270-271. 10.1053/gast.2003.50034.CrossRefPubMed
5.
Thorstensen L, Diep CB, Meling GI, Aagesen TH, Ahrens CH, Rognum TO, Lothe RA: WNT1 inducible signaling pathway protein 3, WISP-3, a novel target gene in colorectal carcinomas with microsatellite instability. Gastroenterology. 2001, 121: 1275-1280. 10.1053/gast.2001.29570.CrossRefPubMed
6.
Kleer CG, Zhang Y, Pan Q, van Golen KL, Wu ZF, Livant D, Merajver SD: WISP3 is a novel tumor suppressor gene of inflammatory breast cancer. Oncogene. 2002, 21: 3172-3180. 10.1038/sj.onc.1205462.CrossRefPubMed
7.
Lin CG, Leu SJ, Chen N, Tebeau CM, Lin SX, Yeung CY, Lau LF: CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family. J Biol Chem. 2003, 278: 24200-24208. 10.1074/jbc.M302028200.CrossRefPubMed
8.
Sakamoto K, Yamaguchi S, Ando R, Miyawaki A, Kabasawa Y, Takagi M, Li CL, Perbal B, Katsube K: The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway. J Biol Chem. 2002, 277: 29399-29405. 10.1074/jbc.M203727200.CrossRefPubMed
9.
Perbal B, Martinerie C, Sainson R, Werner M, He B, Roizman B: The C-terminal domain of the regulatory protein NOVH is sufficient to promote interaction with fibulin 1C: a clue for a role of NOVH in cell-adhesion signaling. Proc Natl Acad Sci USA. 1999, 96: 869-874. 10.1073/pnas.96.3.869.CrossRefPubMedPubMedCentral
10.
11.
Wahab NA, Weston BS, Mason RM: Connective tissue growth factor CCN2 interacts with and activates the tyrosine kinase receptor TrkA. J Am Soc Nephrol. 2005, 16: 340-351. 10.1681/ASN.2003100905.CrossRefPubMed
12.
13.
Gupta N, Wang H, McLeod TL, Naus CC, Kyurkchiev S, Advani S, Yu J, Perbal B, Weichselbaum RR: Inhibition of glioma cell growth and tumorigenic potential by CCN3 (NOV). Mol Pathol. 2001, 54: 293-299. 10.1136/mp.54.5.293.CrossRefPubMedPubMedCentral
14.
Benini S, Perbal B, Zambelli D, Colombo MP, Manara MC, Serra M, Parenza M, Martinez V, Picci P, Scotlandi K: In Ewing's sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type. Oncogene. 2005, 24: 4349-61. 10.1038/sj.onc.1208620.CrossRefPubMed
15.
Fu CT, Bechberger JF, Ozog MA, Perbal B, Naus CC: CCN3 (NOV) interacts with connexin43 in C6 glioma cells: possible mechanism of connexin-mediated growth suppression. J Biol Chem. 2004, 279: 36943-36950. 10.1074/jbc.M403952200.CrossRefPubMed
16.
Gellhaus A, Dong X, Propson S, Maass K, Klein-Hitpass L, Kibschull M, Traub O, Willecke K, Perbal B, Lye SJ, et al: Connexin43 interacts with NOV: a possible mechanism for negative regulation of cell growth in choriocarcinoma cells. J Biol Chem. 2004, 279: 36931-36942. 10.1074/jbc.M404073200.CrossRefPubMed
17.
Glukhova L, Angevin E, Lavialle C, Cadot B, Terrier-Lacombe MJ, Perbal B, Bernheim A, Goguel AF: Patterns of specific genomic alterations associated with poor prognosis in high-grade renal cell carcinomas. Cancer Genet Cytogenet. 2001, 130: 105-110. 10.1016/S0165-4608(01)00477-0.CrossRefPubMed
18.
Tsai MS, Hornby AE, Lakins J, Lupu R: Expression and function of CYR61, an angiogenic factor, in breast cancer cell lines and tumor biopsies. Cancer Res. 2000, 60: 5603-5607.PubMed
19.
Babic AM, Kireeva ML, Kolesnikova TV, Lau LF: CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. Proc Natl Acad Sci USA. 1998, 95: 6355-6360. 10.1073/pnas.95.11.6355.CrossRefPubMedPubMedCentral
20.
Tong X, O'Kelly J, Xie D, Mori A, Lemp N, McKenna R, Miller CW, Koeffler HP: Cyr61 suppresses the growth of non-small-cell lung cancer cells via the beta-catenin-c-myc-p53 pathway. Oncogene. 2004, 23: 4847-4855. 10.1038/sj.onc.1207628.CrossRefPubMed
21.
Tong X, Xie D, O'Kelly J, Miller CW, Muller-Tidow C, Koeffler HP: Cyr61, a member of CCN family, is a tumor suppressor in non-small cell lung cancer. J Biol Chem. 2001, 276: 47709-47714. 10.1074/jbc.M107878200.CrossRefPubMed
22.
Bleau AM, Planque N, Perbal B: CCN proteins and cancer: two to tango. Front Biosci. 2005, 10: 998-1009.CrossRefPubMed
23.
Nessling M, Richter K, Schwaenen C, Roerig P, Wrobel G, Wessendorf S, Fritz B, Bentz M, Sinn HP, Radlwimmer B, et al: Candidate genes in breast cancer revealed by microarray-based comparative genomic hybridization of archived tissue. Cancer Res. 2005, 65: 439-447.PubMed
24.
Chappell SA, Walsh T, Walker RA, Shaw JA: Loss of heterozygosity at chromosome 6q in preinvasive and early invasive breast carcinomas. Br J Cancer. 1997, 75: 1324-1329.CrossRefPubMedPubMedCentral
25.
van Golen KL, Davies S, Wu ZF, Wang Y, Bucana CD, Root H, Chandrasekharappa S, Strawderman M, Ethier SP, Merajver SD: A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin Cancer Res. 1999, 5: 2511-2519.PubMed
26.
Kleer CG, Zhang Y, Pan Q, Gallagher G, Wu M, Wu ZF, Merajver SD: WISP3 and RhoC guanosine triphosphatase cooperate in the development of inflammatory breast cancer. Breast Cancer Res. 2004, 6: R110-R115. 10.1186/bcr755.CrossRefPubMed
27.
Kleer CG, Zhang Y, Pan Q, Merajver SD: WISP3 (CCN6) is a secreted tumor-suppressor protein that modulates IGF signaling in inflammatory breast cancer. Neoplasia. 2004, 6: 179-185. 10.1593/neo.03316.CrossRefPubMedPubMedCentral
28.
Ethier SP, Mahacek ML, Gullick WJ, Frank TS, Weber BL: Differential isolation of normal luminal mammary epithelial cells and breast cancer cells from primary and metastatic sites using selective media. Cancer Res. 1993, 53: 627-635.PubMed
29.
Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T: Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001, 411: 494-498. 10.1038/35078107.CrossRefPubMed
30.
Di Fiore PP, Pierce JH, Kraus MH, Segatto O, King CR, Aaronson SA: erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science. 1987, 237: 178-182.CrossRefPubMed
31.
Di Fiore PP, Pierce JH, Fleming TP, Hazan R, Ullrich A, King CR, Schlessinger J, Aaronson SA: Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells. Cell. 1987, 51: 1063-1070. 10.1016/0092-8674(87)90592-7.CrossRefPubMed
32.
Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC: Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004, 6: 931-940. 10.1038/ncb1173.CrossRefPubMed
33.
Huber MA, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H, Kraut N, Beug H, Wirth T: NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004, 114: 569-581. 10.1172/JCI200421358.CrossRefPubMedPubMedCentral
34.
Nass SJ, Herman JG, Gabrielson E, Iversen PW, Parl FF, Davidson NE, Graff JR: Aberrant methylation of the estrogen receptor and E-cadherin 5' CpG islands increases with malignant progression in human breast cancer. Cancer Res. 2000, 60: 4346-4348.PubMed
35.
Droufakou S, Deshmane V, Roylance R, Hanby A, Tomlinson I, Hart IR: Multiple ways of silencing E-cadherin gene expression in lobular carcinoma of the breast. Int J Cancer. 2001, 92: 404-408. 10.1002/ijc.1208.CrossRefPubMed
36.
Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A: The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000, 2: 84-89. 10.1038/35000034.CrossRefPubMed
37.
Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA: The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000, 2: 76-83. 10.1038/35000025.CrossRefPubMed
38.
Sen M, Cheng YH, Goldring MB, Lotz MK, Carson DA: WISP3-dependent regulation of type II collagen and aggrecan production in chondrocytes. Arthritis Rheum. 2004, 50: 488-497. 10.1002/art.20005.CrossRefPubMed
39.
Surmacz E: Function of the IGF-I receptor in breast cancer. J Mammary Gland Biol Neoplasia. 2000, 5: 95-105. 10.1023/A:1009523501499.CrossRefPubMed
40.
Sachdev D, Hartell JS, Lee AV, Zhang X, Yee D: A dominant negative type I insulin-like growth factor receptor inhibits metastasis of human cancer cells. J Biol Chem. 2004, 279: 5017-5024. 10.1074/jbc.M305403200.CrossRefPubMed
41.
Yee D, Lee AV: Crosstalk between the insulin-like growth factors and estrogens in breast cancer. J Mammary Gland Biol Neoplasia. 2000, 5: 107-115. 10.1023/A:1009575518338.CrossRefPubMed
42.
Lee AV, Gooch JL, Oesterreich S, Guler RL, Yee D: Insulin-like growth factor I-induced degradation of insulin receptor substrate 1 is mediated by the 26S proteasome and blocked by phosphatidylinositol 3'-kinase inhibition. Mol Cell Biol. 2000, 20: 1489-1496. 10.1128/MCB.20.5.1489-1496.2000.CrossRefPubMedPubMedCentral
43.
Lee AV, Hilsenbeck SG, Yee D: IGF system components as prognostic markers in breast cancer. Breast Cancer Res Treat. 1998, 47: 295-302. 10.1023/A:1005915420341.CrossRefPubMed
44.
Resnik JL, Reichart DB, Huey K, Webster NJ, Seely BL: Elevated insulin-like growth factor I receptor autophosphorylation and kinase activity in human breast cancer. Cancer Res. 1998, 58: 1159-1164.PubMed
45.
Turner BC, Haffty BG, Narayanan L, Yuan J, Havre PA, Gumbs AA, Kaplan L, Burgaud JL, Carter D, Baserga R, et al: Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation. Cancer Res. 1997, 57: 3079-3083.PubMed
46.
Byrne C, Colditz GA, Willett WC, Speizer FE, Pollak M, Hankinson SE: Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density. Cancer Res. 2000, 60: 3744-3748.PubMed
47.
Lee AV, Jackson JG, Gooch JL, Hilsenbeck SG, Coronado-Heinsohn E, Osborne CK, Yee D: Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. Mol Endocrinol. 1999, 13: 787-796. 10.1210/me.13.5.787.CrossRefPubMed
48.
Rocha RL, Hilsenbeck SG, Jackson JG, VanDenBerg CL, Weng C, Lee AV, Yee D: Insulin-like growth factor binding protein-3 and insulin receptor substrate-1 in breast cancer: correlation with clinical parameters and disease-free survival. Clin Cancer Res. 1997, 3: 103-109.PubMed
Metadata
Title
Inhibition of CCN6 (WISP3) expression promotes neoplastic progression and enhances the effects of insulin-like growth factor-1 on breast epithelial cells
Authors
Yanhong Zhang
Quintin Pan
Hui Zhong
Sofia D Merajver
Celina G Kleer
Publication date
01-12-2005
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 6/2005
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr1351

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