Skip to main content
SpringerLink
Log in

Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas

  • Review
  • Published:
Journal of Cell Communication and Signaling Aims and scope

Abstract

Located at 6q22–23, Ccn6 (WISP3) encodes for a matrix-associated protein of the CCN family, characterized by regulatory, rather than structural, roles in development and cancer. CCN6, the least studied member of the CCN family, shares the conserved multimodular structure of CCN proteins, as well as their tissue and cell-type specific functions. In the breast, CCN6 is a critical regulator of epithelial-to-mesenchymal transitions (EMT) and tumor initiating cells. Studies using human breast cancer tissue samples demonstrated that CCN6 messenger RNA and protein are expressed in normal breast epithelia but reduced or lost in aggressive breast cancer phenotypes, especially inflammatory breast cancer and metaplastic carcinomas. Metaplastic carcinomas are mesenchymal-like triple negative breast carcinomas, enriched for markers of EMT and stemness. RNAseq analyses of the TCGA Breast Cancer cohort show reduced CCN6 expression in approximately 50% of metaplastic carcinomas compared to normal breast. Our group identified frameshift mutations of Ccn6 in a subset of human metaplastic breast carcinoma. Importantly, conditional, mammary epithelial-cell specific ccn6 (wisp3) knockout mice develop invasive high-grade mammary carcinomas that recapitulate human spindle cell metaplastic carcinomas, demonstrating a tumor suppressor function for ccn6. Our studies on CCN6 functions in metaplastic carcinoma highlight the potential of CCN6 as a novel therapeutic approach for this specific type of breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: Working hypothesis on the tumor suppressor function of CCN6 in breast cancer

Similar content being viewed by others

References

  • Abouharb S, Moulder S (2015) Metaplastic breast cancer: clinical overview and molecular aberrations for potential targeted therapy. Curr Oncol Rep 17:431

    Article  PubMed  Google Scholar 

  • Badve S, Dabbs DJ, Schnitt SJ, Baehner FL, Decker T, Eusebi V, Fox SB, Ichihara S, Jacquemier J, Lakhani SR et al (2011) Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. Mod Pathol 24:157–167

    Article  PubMed  Google Scholar 

  • Barcellos-Hoff MH, Akhurst RJ (2009) Transforming growth factor-beta in breast cancer: too much, too late. Breast Cancer Res 11:202

    Article  PubMed  PubMed Central  Google Scholar 

  • Bernardo GM, Keri RA (2012) FOXA1: a transcription factor with parallel functions in development and cancer. Biosci Rep 32:113–130

    Article  CAS  PubMed  Google Scholar 

  • Bork P (1993) The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett 327:125–130

    Article  CAS  PubMed  Google Scholar 

  • Byun D, Mohan S, Baylink DJ, Qin X (2001) Localization of the IGF binding domain and evaluation of the role of cysteine residues in IGF binding in IGF binding protein-4. J Endocrinol 169:135–143

    Article  CAS  PubMed  Google Scholar 

  • Chappell SA, Walsh T, Walker RA, Shaw JA (1997) Loss of heterozygosity at chromosome 6q in preinvasive and early invasive breast carcinomas. Br J Cancer 75:1324–1329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Caestecker MP, Piek E, Roberts AB (2000) Role of transforming growth factor-beta signaling in cancer (In Process Citation). J Natl Cancer Inst 92:1388–1402

    Article  PubMed  Google Scholar 

  • Devilee FTAP (ed) (2003) Pathology and genetics of tumors of the breast and female genital organs. IARC Press, Lyon

    Google Scholar 

  • Ferguson BW, Gao X, Kil H, Lee J, Benavides F, Abba MC, Aldaz CM (2012) Conditional Wwox deletion in mouse mammary gland by means of two Cre recombinase approaches. PLoS One 7:e36618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujii H, Zhou W, Gabrielson E (1996) Detection of frequent allelic loss of 6q23-q25.2 in microdissected human breast cancer tissues. Genes Chromosom Cancer 16:35–39

    Article  CAS  PubMed  Google Scholar 

  • Grotendorst GR, Duncan MR (2005) Individual domains of connective tissue growth factor regulate fibroblast proliferation and myofibroblast differentiation. FASEB J 19:729–738

    Article  CAS  PubMed  Google Scholar 

  • Hayes MJ, Thomas D, Emmons A, Giordano TJ, Kleer CG (2008) Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast. Clin Cancer Res 14:4038–4044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee JS, Fridlyand J, Sahin A, Agarwal R, Joy C et al (2009) Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res 69:4116–4124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holbourn KP, Acharya KR, Perbal B (2008) The CCN family of proteins: structure-function relationships. Trends Biochem Sci 33:461–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang W, Zhang Y, Varambally S, Chinnaiyan AM, Banerjee M, Merajver SD, Kleer CG (2008) Inhibition of CCN6 (Wnt-1-induced signaling protein 3) down-regulates E-cadherin in the breast epithelium through induction of snail and ZEB1. Am J Pathol 172:893–904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang W, Gonzalez ME, Toy KA, Banerjee M, Kleer CG (2010) Blockade of CCN6 (WISP3) activates growth factor-independent survival and resistance to anoikis in human mammary epithelial cells. Cancer Res 70:3340–3350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang W, Martin EE, Burman B, Gonzalez ME, Kleer CG (2016) The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells. Oncotarget 7:25180–25193

    PubMed  PubMed Central  Google Scholar 

  • Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, Thompson EW (2007) Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression. J Cell Physiol 213:374–383

    Article  CAS  PubMed  Google Scholar 

  • 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 (1999) Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet 23:94–98

    Article  CAS  PubMed  Google Scholar 

  • Imai Y, Moralez A, Andag U, Clarke JB, Busby WH Jr, Clemmons DR (2000) Substitutions for hydrophobic amino acids in the N-terminal domains of IGFBP-3 and -5 markedly reduce IGF-I binding and alter their biologic actions. J Biol Chem 275:18188–18194

    Article  CAS  PubMed  Google Scholar 

  • Jones LP, Buelto D, Tago E, Owusu-Boaitey KE (2011) Abnormal mammary adipose tissue environment of brca1 mutant mice show a persistent deposition of highly vascularized multilocular adipocytes. J Cancer Sci Ther (Suppl 2):004

  • Jun JI, Lau LF (2011) Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat Rev Drug Discov 10:945–963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kleer CG (2016) Dual roles of CCN proteins in breast cancer progression. J Cell Commun Signal 10:217–222

    Article  PubMed  PubMed Central  Google Scholar 

  • Kleer CG, Zhang Y, Pan Q, van Golen KL, Wu ZF, Livant D, Merajver SD (2002) WISP3 is a novel tumor suppressor gene of inflammatory breast cancer. Oncogene 21:3172–3180

    Article  CAS  PubMed  Google Scholar 

  • Kleer CG, Zhang Y, Pan Q, Merajver SD (2004) WISP3 (CCN6) is a secreted tumor-suppressor protein that modulates IGF signaling in inflammatory breast cancer. Neoplasia 6:179–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koker MM, Kleer CG (2004) p63 expression in breast cancer: a highly sensitive and specific marker of metaplastic carcinoma. Am J Surg Pathol 28:1506–1512

    Article  PubMed  Google Scholar 

  • Kubota S, Takigawa M (2013) The CCN family acting throughout the body: recent research developments. Biomol Concepts 4:477–494

    Article  CAS  PubMed  Google Scholar 

  • Kutz WE, Gong Y, Warman ML (2005) WISP3, the gene responsible for the human skeletal disease progressive pseudorheumatoid dysplasia, is not essential for skeletal function in mice. Mol Cell Biol 25:414–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lau LF (2016) Cell surface receptors for CCN proteins. J Cell Commun Signal 10:121–127

    Article  PubMed  PubMed Central  Google Scholar 

  • Li Y, Francia G, Zhang JY (2015) p62/IMP2 stimulates cell migration and reduces cell adhesion in breast cancer. Oncotarget 6:32656–32668

    PubMed  PubMed Central  Google Scholar 

  • Lorenzatti G, Huang W, Pal A, Cabanillas AM, Kleer CG (2011) CCN6 (WISP3) decreases ZEB1-mediated EMT and invasion by attenuation of IGF-1 receptor signaling in breast cancer. J Cell Sci 124:1752–1758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin EE, Huang W, Anwar T, Arellano-Garcia C, Burman B, Guan JL, Gonzalez ME, Kleer CG (2017) MMTV-cre;Ccn6 knockout mice develop tumors recapitulating human metaplastic breast carcinomas. Oncogene 36:2275–2285

    Article  CAS  PubMed  Google Scholar 

  • McAllister KA, Bennett LM, Houle CD, Ward T, Malphurs J, Collins NK, Cachafeiro C, Haseman J, Goulding EH, Bunch D et al (2002) Cancer susceptibility of mice with a homozygous deletion in the COOH-terminal domain of the Brca2 gene. Cancer Res 62:990–994

    CAS  PubMed  Google Scholar 

  • Milanese TR, Hartmann LC, Sellers TA, Frost MH, Vierkant RA, Maloney SD, Pankratz VS, Degnim AC, Vachon CM, Reynolds CA et al (2006) Age-related lobular involution and risk of breast cancer. J Natl Cancer Inst 98:1600–1607

    Article  PubMed  Google Scholar 

  • Morishita A, Zaidi MR, Mitoro A, Sankarasharma D, Szabolcs M, Okada Y, D'Armiento J, Chada K (2013) HMGA2 is a driver of tumor metastasis. Cancer Res 73:4289–4299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamura Y, Cui Y, Fernando C, Kutz WE, Warman ML (2009) Normal growth and development in mice over-expressing the CCN family member WISP3. J Cell Commun Signal 3:105–113

    Article  PubMed  PubMed Central  Google Scholar 

  • Ng CKY, Piscuoglio S, Geyer FC, Burke KA, Pareja F, Eberle CA, Lim RS, Natrajan R, Riaz N, Mariani O et al (2017) The landscape of somatic genetic alterations in metaplastic breast carcinomas. Clin Cancer Res 23:3859–3870

    Article  CAS  PubMed  Google Scholar 

  • Pal A, Huang W, Li X, Toy KA, Nikolovska-Coleska Z, Kleer CG (2012a) CCN6 modulates BMP signaling via the smad-independent TAK1/p38 pathway, acting to suppress metastasis of breast cancer. Cancer Res 72:4818–4828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pal A, Huang W, Toy KA, Kleer CG (2012b) CCN6 knockdown disrupts acinar organization of breast cells in three-dimensional cultures through up-regulation of type III TGF-beta receptor. Neoplasia 14:1067–1074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pang J, Toy KA, Griffith KA, Awuah B, Quayson S, Newman LA, Kleer CG (2012) Invasive breast carcinomas in Ghana: high frequency of high grade, basal-like histology and high EZH2 expression. Breast Cancer Res Treat 135:59–66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parr C, Jiang WG (2006) Hepatocyte growth factor activation inhibitors (HAI-1 and HAI-2) regulate HGF-induced invasion of human breast cancer cells. Int J Cancer 119:1176–1183

    Article  CAS  PubMed  Google Scholar 

  • Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7:415–428

    Article  CAS  PubMed  Google Scholar 

  • Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, Brush J, Taneyhill LA, Deuel B, Lew M et al (1998) 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 U S A 95:14717–14722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perbal B (2001) NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues. Mol Pathol 54:57–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perbal B (2004) CCN proteins: multifunctional signalling regulators. Lancet 363:62–64

    Article  CAS  PubMed  Google Scholar 

  • Perbal BATM (2005) CCN proteins: a new family of cell growth and differentiation regulators. World Scientific Publishers, London

    Book  Google Scholar 

  • Perbal B (2006) The CCN3 protein and cancer. Adv Exp Med Biol 587:23–40

    Article  CAS  PubMed  Google Scholar 

  • Perbal B, Brigstock DR, Lau LF (2003) Report on the second international workshop on the CCN family of genes. Mol Pathol 56:80–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perou CM, Jeffrey SS, van de Rijn M, Rees CA, Eisen MB, Ross DT, Pergamenschikov A, Williams CF, Zhu SX, Lee JC et al (1999) Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci U S A 96:9212–9217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752

    Article  CAS  PubMed  Google Scholar 

  • Pollack JR, Perou CM, Alizadeh AA, Eisen MB, Pergamenschikov A, Williams CF, Jeffrey SS, Botstein D, Brown PO (1999) Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat Genet 23:41–46

    Article  CAS  PubMed  Google Scholar 

  • Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273

    Article  CAS  PubMed  Google Scholar 

  • Radisky DC, Hartmann LC (2009) Mammary involution and breast cancer risk: transgenic models and clinical studies. J Mammary Gland Biol Neoplasia 14:181–191

    Article  PubMed  PubMed Central  Google Scholar 

  • Rakha EA, Tan PH, Varga Z, Tse GM, Shaaban AM, Climent F, van Deurzen CH, Purnell D, Dodwell D, Chan T et al (2015) Prognostic factors in metaplastic carcinoma of the breast: a multi-institutional study. Br J Cancer 112:283–289

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez C, Causse A, Ursule E, Theillet C (2000) At least five regions of imbalance on 6q in breast tumors, combining losses and gains. Genes Chromosom Cancer 27:76–84

    Article  CAS  PubMed  Google Scholar 

  • Rungta S, Kleer CG (2012) Metaplastic carcinomas of the breast: diagnostic challenges and new translational insights. Arch Pathol Lab Med 136:896–900

    Article  PubMed  PubMed Central  Google Scholar 

  • Song Y, Liu X, Zhang G, Song H, Ren Y, He X, Wang Y, Zhang J, Zhang Y, Sun S et al (2013) Unique clinicopathological features of metaplastic breast carcinoma compared with invasive ductal carcinoma and poor prognostic indicators. World J Surg Oncol 11:129

    Article  PubMed  PubMed Central  Google Scholar 

  • Tavassoli FA (1992) Classification of metaplastic carcinomas of the breast. Pathol Annu 27:89–119

  • Toy KA, Valiathan RR, Nunez F, Kidwell KM, Gonzalez ME, Fridman R, Kleer CG (2015) Tyrosine kinase discoidin domain receptors DDR1 and DDR2 are coordinately deregulated in triple-negative breast cancer. Breast Cancer Res Treat 150:9–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turner NC, Reis-Filho JS (2006) Basal-like breast cancer and the BRCA1 phenotype. Oncogene 25:5846–5853

    Article  CAS  PubMed  Google Scholar 

  • Turner NC, Reis-Filho JS, Russell AM, Springall RJ, Ryder K, Steele D, Savage K, Gillett CE, Schmitt FC, Ashworth A et al (2007) BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26:2126–2132

    Article  CAS  PubMed  Google Scholar 

  • van Golen LK, Davies S, Wu ZF, Wang Y, Bucana CD, Root H, Chandrasekharappa S, Strawderman M, Ethier SP, Merajver SD (1999) 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 5:2511–2519

  • Xu X, Wagner KU, Larson D, Weaver Z, Li C, Ried T, Hennighausen L, Wynshaw-Boris A, Deng CX (1999) Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat Genet 22:37–43

    Article  CAS  PubMed  Google Scholar 

  • Yang GP, Lau LF (1991) Cyr61, product of a growth factor-inducible immediate early gene, is associated with the extracellular matrix and the cell surface. Cell Growth Differ 2:351–357

    CAS  PubMed  Google Scholar 

  • Zhang Y, Pan Q, Zhong H, Merajver SD, Kleer CG (2005) Inhibition of CCN6 (WISP3) expression promotes neoplastic progression and enhances the effects of insulin-like growth factor-1 on breast epithelial cells. Breast Cancer Res 7:R1080–R1089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Toy KA, Kleer CG (2012) Metaplastic breast carcinomas are enriched in markers of tumor-initiating cells and epithelial to mesenchymal transition. Mod Pathol 25:178–184

    Article  CAS  PubMed  Google Scholar 

  • Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC (2004) Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 6:931–940

    Article  CAS  PubMed  Google Scholar 

  • Zhou ZN, Sharma VP, Beaty BT, Roh-Johnson M, Peterson EA, Van Rooijen N, Kenny PA, Wiley HS, Condeelis JS, Segall JE (2014) Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo. Oncogene 33:3784–3793

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by NIH/NCI grant R01CA125577 to CGK.

Author information

Authors and Affiliations

  1. Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Mai N. Tran & Celina G. Kleer

Authors
  1. Mai N. Tran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Celina G. Kleer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Celina G. Kleer.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tran, M.N., Kleer, C.G. Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas. J. Cell Commun. Signal. 12, 13–19 (2018). https://doi.org/10.1007/s12079-018-0451-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12079-018-0451-9

Keywords

Search

Navigation