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:

αVβ3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer

Abstract

αvβ3 integrin-overexpression in tumor associated vasculature is a marker of poor prognosis in breast cancer. A positive correlation between αvβ3 integrin and overexpression of Heregulin (HRG), a growth factor associated with breast cancer aggressiveness was recently demonstrated. Here, we addressed the role of αvβ3 in the proliferation and survival of HRG-overexpressing breast cancer models. Expression of the RGD-binding integrins αvβ3, αvβ5 and αvβ6 was assessed in the HRG-overexpressing breast cancer cells MDA-MB-231, Hs578T (231/WT and Hs578T/WT, respectively) and derived cells transfected with the antisense orientation of the HRG-β2 full-length cDNA (231/ASPOOL, 231/AS31 and Hs578T/AS15). Interestingly, only αvβ3 expression was noticeably decreased by blockade of HRG expression in the 231/ASPOOL, 231/AS31 and Hs578T/AS15 cells. Small RGD-based peptidomimetic αvβ3 antagonists significantly decreased cell viability and anchorage-dependent cell growth of HRG-overexpressing cells, while the low-HRG-expressing 231/AS31 cells did not show a significant response. Mechanistically, functional blockade of αvβ3 impaired HRG-promoted hyperactivation of ERK1/ERK2 MAPK without altering the activation of AKT. Flow cytometric analysis of the cell cycle demonstrated that αvβ3 antagonists significantly decreased S- and G2/M-phase subpopulations of 231/WT and control 231/VEC cells. Comparable, this effect was linked to an increase in the levels and nuclear translocation of the CDKs inhibitor p27Kip1. Besides downregulating αvβ3 and its driven signaling, HRG blockade led to decreased levels of CYR61 in 231/ASPOOL and 231/AS31 cells. Considering that CYR61 is sufficient to upregulate the expression of αvβ3, we then assessed αvβ3 levels in MDA-MB-231 cell derivatives expressing the antisense orientation of the CYR61 cDNA (231/CYR61AS-5 and 231/CYR61AS-8). Remarkably, downregulation of CYR61 drastically decreased the levels of αvβ3 in the 231/CYR61-5 and 231/CYR61-8 cells, providing further evidence of a key role for CYR61 in HRG-dependent αvβ3 overexpression. Moreover, blockade of CYR61 expression impaired the HRG-induced hyperactivation of ERK1/ERK2 MAPK without altering the activation status of AKT in MDA-MB-231 cells, thus resembling the effects exerted by the downregulation of HRG expression as well as by functional blockade of αvβ3. These results indicate that HRG is regulating αvβ3 levels as well as αvβ3-triggered signaling through its downstream effector, CYR61, in highly invasive breast cancer cells. Altogether, the data presented here provide evidence of a CYR61-regulatory role on αvβ3 integrin expression in the modulation of uncontrolled growth of HRG-overexpressing breast carcinomas. This work supports additional studies concerning the use of integrin antagonists as dual therapeutic agents in breast cancer, targeting both, endothelial and tumor cells.

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 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Atlas E, Cardillo M, Mehmi I, Zahedkargaran H, Tang C and Lupu R . (2003). Mol. Cancer Res., 1, 165–175.

  • Buerkle MA, Pahernik SA, Sutter A, Jonczyk A, Messmer K and Dellian M . (2002). Br. J. Cancer, 86, 788–795.

  • Butler B, Williams MP and Blystone SD . (2003). J. Biol. Chem., 278, 5264–5270.

  • Carron CP, Meyer DM, Pegg JA, Engleman VW, Nickols MA, Settle SL, Westlin WF, Ruminski PG and Nickols GA . (1998). Cancer Res., 58, 1930–1935.

  • Craig WS, Cheng S, Mullen DG, Blevitt J and Pierchsbacher MD . (1995). Biopolymers, 37, 157–175.

  • Cruet-Hennequart S, Maunbant S, Luis J, Gauduchon P, Staedel C and Dedhar S . (2003). Oncogene, 22, 1688–1702.

  • Felding-Habermann B, O'Toole TE, Smoth JW, Fransvea E, Ruggeri ZM, Guinsberg MH, Hughes PE, Pampori N, Shattil SJ, Saven A and Mueller BM . (2001). Proc. Natl. Acad. Sci. USA, 98, 1853–1858.

  • Gasparini G, Brooks PC, Biganzoli E, Vermeulen PB, Bonoldi E, Dirix LY, Rinieri G, Miceli R and Cheresh DA . (1998). Clin. Cancer Res., 4, 2625–2634.

  • Griggs D, Shannon K, Settle S, Duffin T, Nickols M, Schroeter S, Nickols G and Westlin W . (2001). Proc. Am. Assoc. Cancer Res., 42, 263.

  • Harms JF, Welch DR, Samant RS, Shevde LA, Miele ME, Babu GR, Goldberg SF, Gilman VR, Sosnowski DM, Campo DA, Gay CV, Budgeon LR, Mercer R, Jewell J, Mastro AM, Donahue HJ, Erin N, Debies MT, Meehan WJ, Jones AL, Mbalaviele G, Nickols A, Christensen ND, Melly R, Beck LN, Kent J, Rader RK, Kotyk JJ, Pagel MD, Westlin WF and Griggs DW . (2004). Clin. Exp. Metast., 21, 119–128.

  • Hood J and Cheresh DA . (2002). Nat. Rev. Cancer, 2, 92–98.

  • Hynes RO . (1992). Cell., 69, 11–25.

  • Janssen ML, Oyen WJ, Dijkgraaf I, Masunger LF, Frielink C, Edwards DS, Rajopadhye M, Boonstra H, Corstens FH and Boerman O . (2002). Cancer Res., 62, 6146–6151.

  • Jin H and Varner J . (2004). Br. J. Cancer, 90, 561–565.

  • Leu SJ, Chen N, Chen CC, Todorovic V, Bai T, Juric V, Liu Y, Yan G, Lam SC and Lau LF . (2004). J. Biol. Chem., 279, 44177–44187.

  • Leu SJ, Lam SC and Lau LF . (2002). J. Biol. Chem., 277, 46248–46255.

  • Levkau B, Kenagy RD, Karsan A, Weitkamp B, Clowes AW, Ross A and Raines EW . (2002). Cell Death Differ., 9, 1360–1367.

  • Lin MT, Chang CC, Chen ST, Chang HL, Su JL, Chau JP and Kuo ML . (2004). J. Biol. Chem., 279, 24015–24023.

  • Martin KH, Slack JK, Boerner SA, Martin CC and Parsons JT . (2002). Science, 296, 1652–1653.

  • Menendez JA, Mehmi I, Griggs DW and Lupu R . (2003). Endocrine-Relat. Cancer, 10, 141–152.

  • Menendez JA, Vellon L, Mehmi I, Teng PK, Griggs D and Lupu R . (2004). Oncogene, Dec 13, Epub ahead of print.

  • Meyer D, Nickols G, Pegg J and Westlin W . (2001). Proc. Am. Assoc. Cancer Res., 42, 825.

  • Percheur I, Peyruchaud O, Serre CM, Guglielmi J, Voland C, Bourre F, Margue C, Cohen Solal M, Buffetr A, Kieffer N and Clezadin P . (2002). FASEB J., 16, 1266–1268.

  • Pereira JJ, Meyer T, Docherty SE, Reid HH, Marshall J, Thompson EW, Rossjohn J and Price JT . (2004). Cancer Res., 64, 977–984.

  • Reinmuth N, Liu S, Ahmad SA, Fan F, Stoeltzing O, Parikh AA, Bucana CD, Gallick GE, Nickols MA, Westlin WF and Ellis LM . (2003). Cancer Res., 63, 2079–2087.

  • Roberts MS, Woods AJ, Schaw PE and Norman JC . (2003). J. Biol. Chem., 278, 1975–1985.

  • Rolli M, Fransvea E, Pilch J, Saven A and Felding-Habermann B . (2003). Proc. Natl. Acad. Sci. USA, 100, 9482–9487.

  • Rüegg C, Dormond O and Mariotti A . (2004). Biochim. Biophys. Acta, 1654, 51–67.

  • Schaffner P and Dard MM . (2003). Cell. Mol. Life Sci., 60, 119–132.

  • Schwartz MA and Gingsberg MH . (2002). Nat. Cell Biol., 4, E65–E68.

  • Shannon KE, Keene JL, Settle SL, Duffin TD, Nickols MA, Westlin M, Schroeter S, Ruminski PG and Griggs DW . (2004). Clin. Exp. Metas., 21, 129–138.

  • Stupack DG and Cheresh DA . (2002). J. Cell Sci., 115, 3729–3738.

  • Stupack DG and Cheresh DA . (2003). Oncogene, 22, 9022–9029.

  • Stupack G, Puente XS, Boutsaboualoy S, Storgard CM and Cheresh DA . (2001). J. Cell Biol., 155, 459–470.

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

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

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

  • Tsai MS, Shannon-Taylor LA, Mehmi I, Tang CK and Lupu R . (2003). Oncogene, 22, 761–768.

Download references

Acknowledgements

The authors would like to thank Miaw-Shei Tsai for the generation of the Cyr61 antisense cells and Dr David Griggs for providing the RGD peptidomimetic agents. This work was supported by the breast cancer Auxiliary program at the Evanston Northwestern Healthcare Research Institute (RL) and the NIH award number NIDDK-RO1-0490490 to RL.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vellon, L., Menendez, J. & Lupu, R. αVβ3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer. Oncogene 24, 3759–3773 (2005). https://doi.org/10.1038/sj.onc.1208452

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208452

Keywords

This article is cited by

Search

Quick links