Abstract
Human Cripto-1 (CR-1) is overexpressed in approximately 80% of human breast, colon and lung carcinomas. Mouse Cr-1 upregulation is also observed in a number of transgenic (Tg) mouse mammary tumors. To determine whether CR-1 can alter mammary gland development and/or may contribute to tumorigenesis in vivo, we have generated Tg mouse lines that express human CR-1 under the transcriptional control of the mouse mammary tumor virus (MMTV). Stable Tg MMTV/CR-1 FVB/N lines expressing different levels of CR-1 were analysed. Virgin female MMTV/CR-1 Tg mice exhibited enhanced ductal branching, dilated ducts, intraductal hyperplasia, hyperplastic alveolar nodules and condensation of the mammary stroma. Virgin aged MMTV/CR-1 Tg mice also possessed persistent end buds. In aged multiparous MMTV/CR-1 mice, the hyperplastic phenotype was most pronounced with multifocal hyperplasias. In the highest CR-1-expressing subline, G4, 38% (12/31) of the multiparous animals aged 12–20 months developed hyperplasias and approximately 33% (11/31) developed papillary adenocarcinomas. The long latency period suggests that additional genetic alterations are required to facilitate mammary tumor formation in conjunction with CR-1. This is the first in vivo study that shows hyperplasia and tumor growth in CR-1-overexpressing animals.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Adamson ED, Minchiotti G and Salomon DS . (2002). J. Cell. Physiol., 190, 267–278.
Adkins HB, Bianco C, Schiffer SG, Rayhorn P, Zafari M, Cheung AE, Orozco O, Olson D, De Luca A, Chen LL, Miatkowski K, Benjamin C, Normanno N, Williams KP, Jarpe M, LePage D, Salomon D and Sanicola M . (2003). J. Clin. Invest., 112, 575–587.
Bhattacharya B, Miura, Brandenberger R, Mejido, Luo Y, Yang AX, Joshi BH, Ginis I, Thies RS, Amit M, Lyons, Condie BG, Itskovitz-Eldor J, Rao MS and Puri RK . (2004). Blood, 103, 2956–2964.
Bianco C, Adkins HB, Wechselberger C, Seno M, Normanno N, De Luca A, Sun Y, Khan N, Kenney N, Ebert A, Williams KP, Sanicola M and Salomon DS . (2002). Mol. Cell. Biol., 22, 2586–2597.
Bianco C, Strizzi L, Rehman A, Normanno N, Wechselberger C, Sun Y, Khan N, Hirota M, Adkins H, Williams K, Margolis RU, Sanicola M and Salomon DS . (2003). Cancer Res., 63, 1192–1197.
Botchan M, Topp W and Sambrook J . (1976). Cell, 9, 269–287.
Brisken C, Heineman A, Chavarria T, Elenbaas B, Tan J, Dey SK, McMahon JA, McMahon AP and Weinberg RA . (2000). Genes Dev., 14, 650–654.
Cardiff RD and Munn RJ . (1995). Cancer Lett., 90, 13–19.
Carpenter MK, Rosler ES, Fisk GJ, Brandenberger R, Ares X, Miura T, Lucero T and Rao MS . (2004). Develop. Dyn., 229, 243–258.
Cheng SK, Olale F, Bennett JT, Brivanlou AH and Schier AF . (2003). Genes Dev., 17, 31–36.
Ciardiello F, Dono R, Kim N, Persico MG and Salomon DS . (1991). Cancer Res., 51, 1051–1054.
Ciardiello F, Tortora G, Bianco C, Selvam MP, Basolo F, Fontanini G, Pacifico F, Normanno N, Brandt R and Persico MG . (1994). Oncogene, 9, 291–298.
Ciccodicola A, Dono R, Obici S, Simeone A, Zollo M and Persico MG . (1989). EMBO J., 8, 1987–1991.
Colas JF and Schoenwolf GC . (2000). Gene, 255, 205–217.
Delcommenne M, Tan C, Gray V, Rue L, Woodgett J and Dedhar S . (1998). Proc. Natl. Acad. Sci. USA, 95, 11211–11216.
De Luca A, Casamassimi A, Selvam MP, Losito S, Ciardiello F, Agrawal S, Salomon DS and Normanno N . (1999). Int. J. Cancer, 80, 589–594.
De Luca A, Selvam MP, Sandomenico C, Pepe S, Bianco AR, Ciardiello F, Salomon DS and Normanno N . (1997). Int. J. Cancer, 73, 277–282.
Ding J, Yang L, Yan YT, Chen A, Desai N, Wynshaw-Boris A and Shen MM . (1998). Nature, 395, 702–707.
Donehower LA, Huang AL and Hager GL . (1981). J. Virol., 37, 226–238.
Dono R, Scalera L, Pacifico F, Acampora D, Persico MG and Simeone A . (1993). Development, 118, 1157–1168.
Ebert AD, Wechselberger C, Nees M, Clair T, Schaller G, Martinez-Lacaci I, Wallace-Jones B, Bianco C, Weitzel HK and Salomon DS . (2000). Exp. Cell Res., 257, 223–229.
Feinberg AP and Vogelstein B . (1984). Anal. Biochem., 137, 266–267.
Gray PC, Harrison and Vale V . (2003). Proc. Natl. Acad. Sci. USA, 100, 5193–5198.
Harms PW and Chang C . (2003). Genes Dev., 17, 2624–2629.
Herrington EE, Ram TG, Salomon DS, Johnson GR, Gullick WJ, Kenney N and Hosick HL . (1997). J. Cell Physiol., 170, 47–56.
Howe LR and Brown AM . (2004). Cancer Biol. Ther., 3, 36–41.
Huang AL, Ostrowski MC, Berard D and Hager GL . (1981). Cell, 27, 245–255.
Imbert A, Eelkema R, Jordan S, Feiner H and Cowin P . (2001). J. Cell Biol., 153, 555–568.
Johnson MD, Kenney NJ, Stoica A, Hilakivi-Clarke L, Singh B, Chepko G, Clarke R, Sholler PF, Lirio AA, Foss C, Reiter R, Trock B, Paik S and Martin MB . (2003). Nature Med., 9, 1081–1084.
Kenney NJ, Huang RP, Johnson GR, Wu JX, Okamura D, Matheny W, Kordon E, Gullick WJ, Plowman G and Smith GH . (1995). Mol. Reprod. Dev., 41, 277–286.
Kenney NJ, Smith GH, Johnson MD, Rosenberg K, Salomon DS and Dickson RB . (1997). Pathogenesis, 1, 57–71.
Kenney NJ, Smith GH, Maroulakou IG, Green JH, Muller WJ, Callahan R, Salomon DS and Dickson RB . (1996). Mol. Carcinog., 15, 44–56.
Kinoshita N, Minshull J and Kirschner MW . (1995). Cell, 83, 621–630.
Laird PW, Zijderveld A, Linders K, Rudnicki MA, Jaenisch R and Berns A . (1991). Nucleic Acids Res., 19, 4293.
Landesman-Bollag E, Romieu-Mourez R, Song DH, Sonenshein GE, Cardiff RD and Seldin DC . (2001). Oncogene, 20, 3247–3257.
Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, Rowlands T, Egeblad M, Cowin P, Werb Z, Tan LK, Rosen JM and Varmus HE . (2003). Proc. Natl. Acad. Sci. USA, 100, 15853–15858.
Liu BY, McDermott SP, Khwaja SS and Alexander CM . (2004). Proc. Natl. Acad. Sci. USA, 101, 4158–4163.
Morkel M, Huelsken J, Wakamiya M, Ding J, van de Wetering M, Clevers H, Taketo MM, Behringer RR, Shen MM and Birchmeier W . (2003). Development, 130, 6283–6294.
Naylor MJ and Ormandy CJ . (2002). Dev. Dynam., 225, 100–105.
Niemeyer CC, Persico MG and Adamson ED . (1998). Cell Death Differ., 5, 440–449.
Niemeyer CC, Spencer-Dene B, Wu JX and Adamson ED . (1999). Int. J. Cancer, 81, 588–591.
Normanno N, Bianco C, Damiano V, de Angelis E, Selvam MP, Grassi M, Magliulo G, Tortora G, Bianco AR, Mendelsohn J, Salomon DS and Ciardiello F . (1996). Clin. Cancer Res., 2, 601–609.
Normanno N, Kim N, Wen D, Smith K, Harris AL, Plowman G, Colletta G, Ciardiello F and Salomon DS . (1995). Breast Cancer Res. Treat., 35, 293–297.
Normanno N, Tortora G, De Luca A, Pomatico G, Casamassimi A, Agrawal S, Mendelsohn J, Bianco AR and Ciardiello F . (1999). Oncol. Rep., 6, 1105–1109.
Oloumi A, McPhee and Dedhar S . (2004). Biochim. Biophys. Acta., 1691, 1–15.
Panico L, D'Antonio A, Salvatore G, Mezza E, Tortora G, De Laurentiis M, De Placido S, Giordano T, Merino M, Salomon DS, Mullick WJ, Pettinato G, Schnitt SJ, Bianco AR and Ciardiello F . (1996). Int. J. Cancer, 65, 51–56.
Pollard JW . (2001). Breast Cancer Res., 3, 320–337.
Qi CF, Liscia DS, Normanno N, Merlo G, Johnson GR, Gullick WJ, Ciardiello F, Saeki T, Brandt R and Kim N . (1994). Br. J. Cancer, 69, 903–910.
Robinson GW and Henninghausen L . (1997). Development, 124, 2701–2708.
Robinson GW, Henninghausen L and Johnson PJ . (2000). Genes Dev., 14, 889–894.
Rosner A, Miyoshi K, Landesman-Bollag E, Xu X, Seldin DC, Moser AR, MacLeod CL, Shyamala G, Gillgrass AE and Cardiff RD . (2002). Am. J. Path., 161, 1087–1097.
Salomon DS, Bianco C and De Santis M . (1999). BioEssays, 21, 61–70.
Salomon DS, Bianco C, Ebert AD, Khan NI, De Santis M, Normanno N, Wechselberger C, Seno M, Williams K, Sanicola M, Foley S, Gullick WJ and Persico G . (2000). Endocr. Relat. Cancer, 7, 199–226.
Schier AF and Shen MM . (2000). Nature, 403, 385–389.
Shen MM and Schier AF . (2000). Trends Genet., 16, 303–309.
Shen MM, Wang H and Leder P . (1997). Development, 124, 429–442.
Silberstein GB . (2001). Breast Cancer Res., 3, 218–223.
Soriano, Pepper MS, Orci L and Montesano R . (1998). J. Mammary Gland Biol. Neoplasia, 3, 133–150.
Srinivasan R, Gillett CE, Barnes DM and Gullick WJ . (2000). Cancer Res, 60, 1483–1487.
Strizzi L, Bianco C, Normanno N, Seno M, Wechselberger C, Wallace-Jones B, Khan NI, Hirota M, Sun Y, Sanicola M and Salomon DS . (2004). J. Cell. Physiol., 201, 266–276.
Uyttendale H, Sorian JV, Montesano R and Kitajewski J . (1998). Dev. Biol., 196, 204–217.
Webster MA, Martin-Soudant N, Nepveu A, Cardiff RD and Muller WJ . (1998). Oncogene, 16, 1963–1972.
Wechselberger C, Ebert AD, Bianco C, Khan NI, Sun Y, Wallace-Jones B, Montesano R and Salomon DS . (2001). Exp. Cell Res., 266, 95–105.
Wechselberger C, Kreil G and Richter K . (1992). Proc. Natl. Acad. Sci. USA, 89, 9819–9822.
White DE, Cardiff RD, Dedhar S and Muller WJ . (2001). Oncogene, 20, 7064–7072.
Xing PX, Hu XF, Hosick HL and McKenzie IFC . (2004). Cancer Res., 64, 4018–4023.
Xu C, Liguori G, Persico MG and Adamson ED . (1999). Development, 126, 483–494.
Yan YT, Liu JJ, Luo Y, E C, Haltiwanger RS, Abate-Shen C and Shen MM . (2002). Mol. Cell. Biol., 22, 4439–4449.
Yeo C and Whitman M . (2001). Mol. Cell, 7, 949–957.
Yokota C, Kofron M, Zuck M, Houston DW, Isaacs H, Asashima M, Wylie CC and Heasman J . (2003). Development, 130, 2199–2212.
Zhang J, Talbot WS and Schier AF . (1998). Cell, 92, 241–251.
Acknowledgements
We thank Dr Lionel Feigenbaum (SAIC Frederick) for generating the MMTV-CR-1 transgenic FVB/N mice and Amanda Kalmanowicz and Heidi Olesch from the Building 28 mouse facility at NIH for excellent animal care. We also thank Dr Humphrey Gardner of the Biogen Idec Department of Research Pathology for review of the MMTV/CR-1 histology slides. We gratefully acknowledge the generosity of Dr Yi Li (Baylor College of Medicine) for providing slides of the MMTV/Wnt-1 mammary tumors. This work was supported in part by funding from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to Nicola Normanno.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wechselberger, C., Strizzi, L., Kenney, N. et al. Human Cripto-1 overexpression in the mouse mammary gland results in the development of hyperplasia and adenocarcinoma. Oncogene 24, 4094–4105 (2005). https://doi.org/10.1038/sj.onc.1208417
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208417
Keywords
This article is cited by
-
CRIPTO antagonist ALK4L75A-Fc inhibits breast cancer cell plasticity and adaptation to stress
Breast Cancer Research (2020)
-
Dynamic regulation of the cancer stem cell compartment by Cripto-1 in colorectal cancer
Cell Death & Differentiation (2015)
-
Cripto-1 expression and its prognostic value in human bladder cancer patients
Tumor Biology (2015)
-
Pubertal high fat diet: effects on mammary cancer development
Breast Cancer Research (2013)
-
Expression and functional role of CRIPTO-1 in cutaneous melanoma
British Journal of Cancer (2011)