Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Mammary gland development requires syndecan-1 to create a β-catenin/TCF-responsive mammary epithelial subpopulation

Oncogene volume 22, pages 9243–9253 (2003)Cite this article

Abstract

Mice with a null mutation in the cell surface heparan sulfate (HS) proteoglycan, syndecan-1 (Sdc1), develop almost normally, but resist mammary tumor development in response to Wnt-1. Here, we test the hypothesis that Sdc1 promotes Wnt-1-induced tumor development by interacting with the Wnt cell surface signaling complex. Thus, the response of Sdc1−/− mammary epithelial cells (mecs) to the intracellular, activated Wnt signal transducer, ΔNβ-catenin, was assayed both in vitro and in vivo, to test whether β-catenin/TCF transactivation was Sdc1-independent. Surprisingly, we found that the expression of a canonical Wnt pathway reporter, TOP-FLASH, was reduced by 50% in both unstimulated Sdc1−/− mecs and in stimulated cells responding to Wnt1 or ΔNβ-catenin. Tumor development in response to ΔNβ-catenin was also significantly delayed on a Sdc1−/− background. Furthermore, the average β-catenin/TCF transactivation per cell was normal in Sdc1−/− mec cultures, but the number of responsive cells was reduced by 50%. Sdc1−/− mecs show compensatory changes that maintain the number of HS chains, hence these experiments cannot test the coreceptor activity of HS for Wnt signaling. We propose that TCF-dependent transactivational activity is suppressed in 50% of cells in Sdc1−/− glands, and conclude that the major effect of Sdc1 does not map to the activity of the Wnt signaling complex, but to another pathway to create or stabilize the β-catenin/TCF-responsive tumor precursor cells in mouse mammary gland.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Abbreviations

HS:

heparan sulfate

HSPG:

heparan sulfate proteoglycan

Sdc1:

syndecan-1

wg:

wingless

Fz:

frizzled receptor

mecs:

mammary epithelial cells

ΔNβcat:

[ΔN89]-β-catenin

References

  • Alexander CM, Reichsman F, Hinkes MT, Lincecum J, Becker KA, Cumberledge S and Bernfield M . (2000). Nat. Genet., 25, 329–332.

  • Baeg G-H, Lin X, Khare N, Baumgartner S and Perrimon N . (2001). Development, 128, 87–94.

  • Baeg G-H and Perrimon N . (2000). Curr. Opin. Cell Biol., 12, 575–580.

  • Bafico A, Liu G, Yaniv A, Gazit A and Aaronson SA . (2001). Nature Cell Biology, 3, 683–686.

  • Behrens J . (2000). J. Cell Sci., 113, 911–919.

  • Bernfield M, Gotte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J and Zako M . (1999). Annu. Rev. Biochem., 68, 729–777.

  • Bienz M and Clevers H . (2000). Cell, 103, 311–320.

  • Bradley RS and Brown AMC . (1990). EMBO J., 9, 1569–1575.

  • Bradley RS and Brown AM . (1995). Mol. Cell. Biol., 15, 4616–4622.

  • Brantjes H, Barker N, Van Es J and Clevers H . (2002). Biol. Chem., 383, 255–261.

  • Burrus LW and McMahon AP . (1995). Exp. Cell Res., 220, 363–373.

  • Chan S-K and Struhl G . (2002). Cell, 111, 265–280.

  • Clevers H . (2000). Nat. Genet., 24, 206–208.

  • Cumberledge S and Reichsman F . (1997). Trends Genet., 13, 421–423.

  • Emerman JT and Bissell MJ . (1988). Adv. Cell Culture, 6, 137–159.

  • Hovanes K, Li TWH, Munguia JE, Truong T, Milovanovic T, Marsh JL, Holcombe RF and Waterman ML . (2001). Nat. Genet., 28, 53–57.

  • Imbert A, Eelkema R, Jordan S, Feiner H and Cowin P . (2001). J. Cell Biol., 153, 555–568.

  • Ishitani T, Ninomiya-Tsuji J, Nagai S-I, Nishita M, Meneghini M, Barker N, Waterman M, Bowerman B, Clevers H, Shibuya H and Matsumoto K . (1999). Nature, 399, 798–802.

  • Ishitani T, Ninomiya-Tsuji J and Matsumoto K . (2003). Mol. Cell. Biol., 23, 1379–1389.

  • Letamendia A, Labbe E and Attisano L . (2001). J. Bone Joint Surg. (Amer.), 83-A, S31–39.

  • Lin X, Buff EM, Perrimon N and Michelson AM . (1999). Development, 126, 3715–3723.

  • Lin X and Perrimon N . (1999). Nature, 400, 281–284.

  • Lustig B, Jerchow B, Sachs M, Weiler S, Peitsch T, Karsten U, van de Wetering M, Clevers H, Schlag PM, Birchmeier W and Behrens J . (2002). Mol. Cell. Biol., 22, 1184–1193.

  • Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A and Niehrs C . (2001). Nature, 411, 321–325.

  • Michaelson JS and Leder P . (2001). Oncogene, 20, 5093–5099.

  • Miller JR, Hocking AM, Brown JD and Moon RT . (1999). Oncogene, 18, 7860–7872.

  • Nishita M, Hashimoto MK, Ogata S, Laurent MN, Ueno N, Shibuya H and Cho KW . (2000). Nature, 403, 781–785.

  • Ornitz DM . (2000). Bioessays, 22, 108–112.

  • Payre F, Vincent A and Carreno S . (1999). Nature, 400, 271–275.

  • Perrimon N and Bernfield M . (2000). Nature, 404, 725–728.

  • Polakis P . (2000). Genes Dev., 14, 1837–1851.

  • Rasmussen SB, Young LJT, and Smith GH . (2000). Methods in Mammary Gland Biology and Breast Cancer Research, Ip MM and Asch BB (eds). Kluwer Academic/Plenum: New York.

    Google Scholar 

  • Reichsman F, Smith L and Cumberledge S . (1996). J. Cell Biol., 135, 819–827.

  • Roose J, Huls G, van Beest M, Moerer P, van der Horn K, Goldschmeding R, Logtenberg T and Clevers H . (1999). Science, 285, 1923–1926.

  • Shimizu H, Julius MA, Giarre M, Zheng Z, Brown AM and Kitajewski J . (1997). Cell Growth Differ., 8, 1349–1358.

  • Stepp MA, Gibson HE, Gala PH, Iglesia DDS, Pajoohesh-Ganji A, Pal-Ghosh S, Brown M, Aquino C, Schwartz AM, Goldberger O, Hinkes MT and Bernfield M . (2002). J. Cell Sci., 115, 4517–4531.

  • Tsuda M, Kamimura K, Nakato H, Archer M, Starn W, Fox B, Humphrey M, Olson S, Futch T, Kaluza V, Siegfried E, Staatz and Selleck SB . (1999). Nature, 400, 276–280.

  • van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, Tjon-Pon-Fong M, Moerer P, van den Born M, Soete G, Pals S, Eilers M, Medema R and Clevers H . (2002). Cell, 111, 241–250.

Download references

Acknowledgements

Thanks to Ann Wozniak for determination of genotypes of transgenic mice. Thanks to Kathy Schell, Pamela Whitney and Joan Batchelder at the University of Wisconsin Flow Cytometry for their expertise and hard work. Thanks also to Sarah Millar for giving us a dkk1 clone before publication. This work is supported by NIH Grant CA 90877-01, a grant from the American Cancer Society (IRG-58-011-43-01), the University of Wisconsin Cancer Center Support Grant (P30 CA14520), a training award for BL (T32 CA09135) and an award from the Howard Hughes Medical Institute Research Resources Program for Medical Schools.

Author information

Authors and Affiliations

  1. McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, 1400 University Ave, Madison, WI, USA

    Bob Y Liu, Young Chul Kim, Vicki Leatherberry & Caroline M Alexander

  2. Department of Cell Biology, New York University Medical Center, 550 First Ave, New York, NY, USA

    Pam Cowin

Authors
  1. Bob Y Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Young Chul Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vicki Leatherberry
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pam Cowin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Caroline M Alexander
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Caroline M Alexander.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, B., Kim, Y., Leatherberry, V. et al. Mammary gland development requires syndecan-1 to create a β-catenin/TCF-responsive mammary epithelial subpopulation. Oncogene 22, 9243–9253 (2003). https://doi.org/10.1038/sj.onc.1207217

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207217

Keywords

This article is cited by

Search

Advanced search

Quick links