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.

Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer

Abstract

The growth factor heregulin (HRG), expressed in about 30% of breast cancer tumors, activates the erbB-2 receptor via induction of heterodimeric complexes of erbB-2 with erbB-3 or erbB-4. HRG induces tumorigenicity and metastasis of breast cancer cells. Our investigation into whether HRG is a factor likely to promote tumor formation independently of erbB-2 overexpression concludes that blockage of HRG expression suppresses the aggressive phenotype of MDA-MB-231 breast cancer cells by inhibiting cell proliferation, preventing anchorage-independent growth, and suppressing the invasive potential of the cells in vitro. More importantly, we observed a marked reduction in tumor formation, tumor size, and a lack of metastasis in vivo. These studies were achieved by blocking HRG expression in MDA-MB-231 cells using an HRG antisense cDNA. In the search for the mechanism by which blockage of HRG reverts this aggressive phenotype, we discovered that the cells in which HRG is blocked exhibit a marked decrease in erbB activation and a significant reduction in MMP-9 activity, demonstrating a direct causal role in HRG induction of tumorigenicity. Our study is the first report and serves as a proof of the concept that HRG is a key promoter of breast cancer tumorigenicity and metastasis independently of erbB-2 overexpression and should be deemed a potential target in developing therapies for breast cancer.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 2
Figure 3
Figure 4

References

  • Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA, Di Fiore PP and Kraus MH . (1995). Oncogene, 10, 1813–1821.

  • Atlas E, Cardillo M, Mehmi I, Zahedkargaran H, Tang C and Lupu R . In Press: Molecular Cancer Research (2003).

  • Bacus SS, Huberman E, Chin D, Kiguchi K, Simpson S, Lippman M and Lupu R . (1992). Cell Growth Differ., 3, 401–411.

  • Cardillo M, Tang CK and Lupu R. Heregulin induces a metastatic phenotype to breast cancer cells in vivo. American Association for Cancer Research. March 1995, Toronto, Canada.

  • Chen X, Levkowitz G, Tzahar E, Karunagaran D, Lavi S, Ben-Baruch N, Leitner O, Ratzkin BJ, Bacus SS and Yarden Y . (1996). J. Biol. Chem., 271, 7620–7629.

  • Curran S and Murray GI . (1999). J. Pathol., 189, 300–308.

  • Grunt TW, Saceda M, Martin MB, Lupu R, Dittrich E, Krupitza G, Harant H, Huber H and Dittrich C . (1995). Int. J. Cancer, 63, 560–567.

  • Guerra-Vladusic FK, Scott G, Weaver V, Vladusic EA, Tsai MS, Benz CC and Lupu R . (1999). Int. J. Oncol., 15, 883–892.

  • Hijazi MM, Thompson EW, Tang C, Coopman P, Torri JA, Yang D, Mueller SC and Lupu R . (2000). Int. J. Oncol. 17, 629–641.

  • Himelstein BP, Lee EJ, Sato H, Seiki M and Muschel RJ . (1997). Oncogene, 14, 1995–1998.

  • Hua J and Muschel RJ . (1996). Cancer Res., 56, 5279–5284.

  • Lee KS, Rha SY, Kim SJ, Kim JH, Roh JK, Kim BS and Chung HC . (1996). Clin. Exp. Metastasis, 14, 512–519.

  • Lim SJ, Lopez-Berestein G, Hung MC, Lupu R and Tari AM . (2000). Oncogene, 19, 6271–6276.

  • Liu W, Guerra-Vladusic FK, Kurakata S, Lupu R and Kohwi-Shigematsu T . (1999). Cancer Res., 59, 5695–5703.

  • Lupu R, Colomer R, Zugmaier G, Sarup J, Shepard M, Slamon D and Lippman ME . (1990). Science, 249, 1552–1555.

  • Lupu R, Cardillo M, Harris L, Hijazi M and Rosenberg K . (1995). Semin. Cancer Biol., 6, 135–145.

  • Lupu R, Colomer R, Kannan B and Lippman ME . (1992a). Proc. Natl. Acad. Sci. USA, 89, 2287–2291.

  • Lupu R, Wellstein A, Sheridan J, Ennis BW, Zugmaier G, Katz D, Lippman ME and Dickson RB . (1992b). Biochemistry, 31, 7330–7340.

  • Paik S, Hazan R, Fisher ER, Sass RE, Fisher B, Redmond C, Schlessinger J, Lippman ME and King CR . (1990). J. Clin. Oncol., 8, 103–112.

  • Pierce JH, Arnstein P, DiMarco E, Artrip J, Kraus MH, Lonardo F, Di Fiore PP and Aaronson SA . (1991). Oncogene, 6, 1189–1194.

  • Plowman GD, Green JM, Culouscou JM, Carlton GW, Rothwell VM and Buckley S . (1993). Nature, 366, 473–475.

  • Reese DM and Slamon DJ . (1997). Stem Cells, 15, 1–8.

  • Sepp-Lorenzino L, Eberhard I, Ma Z, Cho C, Serve H, Liu F, Rosen N and Lupu R . (1996). Oncogene, 12, 1679–1687.

  • Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A and McGuire WL . (1987). Science, 235, 177–182.

  • Sliwkowski MX, Schaefer G, Akita RW, Lofgren JA, Fitzpatrick VD, Nuijens A, Fendly BM, Cerione RA, Vandlen RL and Carraway III KL . (1994). J. Biol. Chem., 269, 14661–14665.

  • Sommers CL, Byers SW, Thompson EW, Torri JA and Gelmann EP . (1994). Breast Cancer Res. Treat., 31, 325–335.

  • Stern DF . (2000). Breast Cancer Res., 2, 176–183.

  • Tang CK, Perez C, Grunt T, Waibel C, Cho C and Lupu R . (1996). Cancer Res., 56, 3350–3358.

  • Tripathy D and Benz CC . (1992). Cancer Treat. Res., 63, 15–60.

  • Tsai MS, Hornby AE, Lakins J and Lupu R . (2000). Cancer Res., 60, 5603–5607.

  • Tsai MS, Bogart DF, Costanede J, Li P and Lupu R . (2002). Oncogene, 21, 8178–8185.

  • Tsang KJ and Crowe DL . (2001). Int. J. Oncol., 18, 369–374.

  • Yao J, Xiong S, Klos K, Nguyen N, Grijalva R, Li P and Yu D . (2001). Oncogene, 56, 8066–8074.

Download references

Acknowledgements

We thank Dr. Marina Cardillo for the histopathological guidance and help Kevin Peet for editorial support and Dr Ella Atlas for scientific discussions. This work was supported by grants from the National Institutes of Health (DK49049), and from the Department of Energy (DE-AC03-76SF00098). M-S Tsai and LA Shamon-Taylor were the recipients of the Breast Cancer Research Program Postdoctoral Traineeship from the Department of Defense.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ruth Lupu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsai, MS., Shamon-Taylor, L., Mehmi, I. et al. Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer. Oncogene 22, 761–768 (2003). https://doi.org/10.1038/sj.onc.1206130

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206130

Keywords

This article is cited by

Search

Quick links