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:

Gene expression profiling of ErbB receptor and ligand-dependent transcription

Oncogene volume 23, pages 1428–1438 (2004)Cite this article

Abstract

Overexpression of ErbB2 and ErbB4 receptors in breast cancers may be accompanied by contrasting clinical outcomes. To investigate the molecular mechanisms contributing to these differences, we undertook a comparative study of gene expression regulated by the two receptors. Agonistic antibodies were employed to activate ErbB2 and ErbB4 in isolation from the other ErbBs in breast cancer cells. Gene expression profiling using a 16 755-gene oligonucleotide array was performed to identify transcriptional targets of receptor activation. Our results indicate that, in the same cell line, ErbB2 and ErbB4 activation influence gene transcription differentially. Although there are genes that are regulated by signaling from both receptors, there are also receptor-specific targets that are preferentially regulated by each receptor. We further show that two ligands acting via the same receptor homodimer may activate different subsets of genes. Many of the induced genes are hitherto unidentified targets of ErbB signaling. These include ErbB4 targets EPS15R, GATA4, and RAB2 and ErbB2-activated HRY/HES1 and PPAP2A. Targets of ErbB2 homodimer signaling may be especially important as markers in breast cancer, where ErbB2 homodimerization mediated by overexpression and ligand-independent activation is common.

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

Similar content being viewed by others

References

  • Alaoui-Jamali MA, Song DJ, Benlimame N, Yen L, Deng X, Hernandez-Perez M and Wang T . (2003). Cancer Res., 63, 3764–3774.

  • Andrechek ER, Laing MA, Girgis-Gabardo AA, Siegel PM, Cardiff RD and Muller WJ . (2003). Cancer Res., 63, 4920–4926.

  • Bacus SS, Chin D, Zelnick CR and Stern DF . (1996). Am. J. Pathol., 148, 549–558.

  • Baulida J, Kraus M, Alimandi M, Di Fiore P and Carpenter G . (1996). J. Biol. Chem., 271, 5251–5257.

  • Burke CL and Stern DF . (1998). Mol. Cell. Biol., 18, 5371–5379.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Chuaqui RF, Bonner RF, Best CJ, Gillespie JW, Flaig MJ, Hewitt SM, Phillips JL, Krizman DB, Tangrea MA, Ahram M, Linehan WM, Knezevic V and Emmert-Buck MR . (2002). Nat. Genet., 32, 509–514.

  • Cohen B, Green J, Foy L and Fell H . (1996). J. Biol. Chem., 271, 4813–4818.

  • da Silva AJ, Brickelmaier M, Majeau GR, Lukashin AV, Peyman J, Whitty A and Hochman PS . (2002). J. Interferon Cytokine Res., 22, 173–188.

  • Decker SJ . (1990). Biochem. Biophys. Res. Commun., 66, 615–621.

  • DiFiore PP, Pierce JH, Kraus MH, Segatto O, King CR and Aaronson SA . (1987). Science, 237, 178–182.

    Article  CAS  Google Scholar 

  • Dupont J, Dunn SE, Barrett JC and LeRoith D . (2003). Recent Prog. Horm. Res., 58, 325–342.

  • Dupont J, Khan J, Qu BH, Metzler P, Helman L and LeRoith D . (2001). Endocrinology, 142, 4969–4975.

    Article  CAS  Google Scholar 

  • Evans PC, Taylor ER, Coadwell J, Heyninck K, Beyaert R and Kilshaw PJ . (2001). Biochem. J., 357, 617–623.

    Article  CAS  Google Scholar 

  • Fambrough D, McClure K, Kazlauskas A and Lander ES . (1999). Cell, 97, 727–741.

    Article  CAS  Google Scholar 

  • Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ and Lemmon MA . (2003). Mol. Cell, 11, 507–517.

  • Gassmann M, Casagranda F, Orioli D, Simon H, Lai C, Klein R and Lemke G . (1995). Nature, 378, 390–394.

    Article  CAS  Google Scholar 

  • Geymayer S and Doppler W . (2000). FASEB J., 14, 1159–1170.

  • Graus-Porta D, Beerli R, Daly J and Hynes N . (1997). EMBO J., 16, 1647–1655.

  • Graus-Porta D, Beerli RR and Hynes NE . (1995). Mol. Cell. Biol., 15, 1182–1191.

    Article  CAS  Google Scholar 

  • Halgren RG, Fielden MR, Fong CJ and Zacharewski TR . (2001). Nucleic Acids Res., 29, 582–588.

  • Hirata H, Yoshiura S, Ohtsuka T, Bessho Y, Harada T, Yoshikawa K and Kageyama R . (2002). Science, 298, 840–843.

    Article  CAS  Google Scholar 

  • Hobbs SS, Coffing SL, Le AT, Cameron EM, Williams EE, Andrew M, Blommel EN, Hammer RP, Chang H and Riese II DJ . (2002). Oncogene, 21, 8442–8452.

  • Hynes NE and Stern DF . (1994). Biochem. Biophys. Acta Rev. Cancer, 1198, 165–184.

  • Jones FE and Stern DF . (1999). Oncogene, 18, 3481–3490.

    Article  CAS  Google Scholar 

  • Jones FE, Welte T, Fu XY and Stern DF . (1999). J. Cell Biol., 147, 77–88.

  • Kew TY, Bell JA, Pinder SE, Denley H, Srinivasan R, Gullick WJ, Nicholson RI, Blamey RW and Ellis IO . (2000). Br. J. Cancer, 82, 1163–1170.

  • Knowlden J, Gee J, Seery L, Farrow L, Gullick W, Ellis I, Blamey R, Robertson J and Nicholson R . (1998). Oncogene, 17, 1949–1957.

    Article  CAS  Google Scholar 

  • Kumar-Sinha C, Ignatoski KW, Lippman ME, Ethier SP and Chinnaiyan AM . (2003). Cancer Res., 63, 132–139.

  • Lee K-F, Simon H, Chen H, Bates B, Hung M-C and Hauser C . (1995). Nature, 378, 394–398.

    Article  CAS  Google Scholar 

  • Lenferink AE, Pinkas-Kramarski R, van de Poll ML, van Vugt MJ, Klapper LN, Tzahar E, Waterman H, Sela M, van Zoelen EJ and Yarden Y . (1998). EMBO J., 17, 3385–3397.

  • Lesa GM and Sternberg PW . (1997). Mol. Biol. Cell, 8, 779–793.

  • Li L, Cleary S, Mandarano MA, Long W, Birchmeier C and Jones FE . (2002). Oncogene, 21, 4900–4907.

    Article  CAS  Google Scholar 

  • Mackay A, Jones C, Dexter T, Silva RL, Bulmer K, Jones A, Simpson P, Harris RA, Jat PS, Neville AM, Reis LF, Lakhani SR and O'Hare MJ . (2003). Oncogene, 22, 2680–2688.

    Article  CAS  Google Scholar 

  • Marshall CJ . (1995). Cell, 80, 179–185.

    Article  CAS  Google Scholar 

  • Mulligan C, Rochford J, Denyer G, Stephens R, Yeo G, Freeman T, Siddle K and O'Rahilly S . (2002). J. Biol. Chem., 277, 42480–42487.

    Article  CAS  Google Scholar 

  • Muthuswamy SK, Li D, Lelievre S, Bissell MJ and Brugge JS . (2001). Nat. Cell Biol., 3, 785–792.

  • Neve RM, Holbro T and Hynes NE . (2002). Oncogene, 21, 4567–4576.

    Article  CAS  Google Scholar 

  • Oh JJ, Grosshans DR, Wong SG and Slamon DJ . (1999). Nucleic Acids Res., 27, 4008–4017.

  • Ohtsuka T, Ishibashi M, Gradwohl G, Nakanishi S, Guillemot F and Kageyama R . (1999). EMBO J, 18, 2196–2207.

  • Olayioye MA, Graus-Porta D, Beerli RR, Rohrer J, Gay B and Hynes NE . (1998). Mol. Cell. Biol., 18, 5042–5051.

    Article  CAS  Google Scholar 

  • Olayioye MA, Neve RM, Lane HA and Hynes NE . (2000). EMBO J., 19, 3159–3167.

  • Ota T, Fujii M, Sugizaki T, Ishii M, Miyazawa K, Aburatani H and Miyazono K . (2002). J. Cell. Physiol., 193, 299–318.

    Article  CAS  Google Scholar 

  • Pawson T and Saxton TM . (1999). Cell, 97, 675–678.

    Article  CAS  Google Scholar 

  • Penington DJ, Bryant I and Riese II DJ . (2002). Cell Growth Differ., 13, 247–256.

  • Perou CM, Jeffrey SS, van de Rijn M, Rees CA, Eisen MB, Ross DT, Pergamenschikov A, Williams CF, Zhu SX, Lee JC, Lashkari D, Shalon D, Brown PO and Botstein D . (1999). Proc. Natl. Acad. Sci. USA, 96, 9212–9217.

  • Plowman G, Green J, Culouscou J-M, Carlton G, Rothwell V and Buckley S . (1993). Nature, 366, 473–475.

    Article  CAS  Google Scholar 

  • Pollard JW and Hennighausen L . (1994). Proc. Natl. Acad. Sci. USA, 91, 9312–9316.

  • Pupa SM, Menard S, Morelli D, Pozzi B, De Palo G and Colnaghi MI . (1993). Oncogene, 8, 2917–2923.

  • Rangel LB, Agarwal R, D'Souza T, Pizer ES, Alo PL, Lancaster WD, Gregoire L, Schwartz DR, Cho KR and Morin PJ . (2003). Clin. Cancer Res., 9, 2567–2575.

  • Richer JK, Jacobsen BM, Manning NG, Abel MG, Wolf DM and Horwitz KB . (2002). J. Biol. Chem., 277, 5209–5218.

  • Riese DI, van Raaij T, Plowman G, Andrews G and Stern D . (1995). Mol. Cell. Biol., 15, 5770–5776.

    Article  CAS  Google Scholar 

  • Riese II DJ and Stern DF . (1998). BioEssays, 20, 41–48.

    Article  Google Scholar 

  • Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, Spellman P, Iyer V, Jeffrey SS, Van de Rijn M, Waltham M, Pergamenschikov A, Lee JC, Lashkari D, Shalon D, Myers TG, Weinstein JN, Botstein D and Brown PO . (2000). Nat. Genet., 24, 227–235.

  • Sapi E, Flick MB, Rodov S, Carter D and Kacinski BM . (1998). J. Soc. Gynecol. Investig., 5, 94–101.

  • Sartor CI, Zhou H, Kozlowska E, Guttridge K, Kawata E, Caskey L, Harrelson J, Hynes N, Ethier S, Calvo B and Earp III HS . (2001). Mol. Cell. Biol., 21, 4265–4275.

  • Sasai Y, Kageyama R, Tagawa Y, Shigemoto R and Nakanishi S . (1992). Genes Dev., 6, 2620–2634.

  • Schroeder JA and Lee DC . (1998). Cell Growth Differ., 9, 451–464.

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

    Article  CAS  Google Scholar 

  • Srinivasan R, Poulsom R, Hurst H and Gullick W . (1997). J. Pathol., 185, 236–245.

  • Stancovski I, Hurwitz E, Leitner O, Ullrich A, Yarden Y and Sela M . (1991). Proc. Natl. Acad. Sci. USA, 88, 8691–8695.

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

  • Stern DF . (2003). Exp. Cell Res., 284, 89–98.

  • Suo Z, Risberg B, Kalsson MG, Willman K, Tierens A, Skovlund E and Nesland JM . (2002). J. Pathol., 196, 17–25.

  • Sweeney C, Fambrough D, Huard C, Diamonti AJ, Lander ES, Cantley LC and Carraway III KL . (2001). J. Biol. Chem., 276, 22685–22698.

    Article  CAS  Google Scholar 

  • Sweeney C, Lai C, Riese II DJ, Diamonti AJ, Cantley LC and Carraway III KL . (2000). J. Biol. Chem., 275, 19803–19807.

    Article  CAS  Google Scholar 

  • Tang CK, Concepcion XZ, Milan M, Gong X, Montgomery E and Lippman ME . (1999). Cancer Res., 59, 5315–5322.

  • Taylor E, Cogdell D, Coombes K, Hu L, Ramdas L, Tabor A, Hamilton S and Zhang W . (2001). Biotechniques, 31, 62–65.

    Article  CAS  Google Scholar 

  • Tidcombe H, Jackson-Fisher A, Mathers K, Stern DF, Gassman M and Golding JP . (2003). Proc. Natl. Acad. Sci. USA, 100, 8281–8286.

  • Tisdale EJ . (1999). Mol. Biol. Cell, 10, 1837–1849.

  • Tseng GC, Oh MK, Rohlin L, Liao JC and Wong WH . (2001). Nucleic Acids Res., 29, 2549–2557.

  • Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ and Yarden Y . (1996). Mol. Cell. Biol., 16, 5276–5287.

    Article  CAS  Google Scholar 

  • Vadlamudi RK, Wang RA, Talukder AH, Adam L, Johnson R and Kumar R . (2000). Mol. Cell. Biol., 20, 9092–9101.

  • Vecchi M, Baulida J and Carpenter G . (1996). J. Biol. Chem., 271, 18989–18995.

    Article  CAS  Google Scholar 

  • Vogt U, Bielawski K, Schlotter C, Bosse U, Falkiewicz B and Podhajska A . (1998). Gene, 223, 375–380.

    Article  CAS  Google Scholar 

  • Waterman H, Sabanai I, Geiger B and Yarden Y . (1998). J. Biol. Chem., 273, 13819–13827.

    Article  CAS  Google Scholar 

  • Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A, Osborne BA, Gottipati S, Aster JC, Hahn WC, Rudolf M, Siziopikou K, Kast WM and Miele L . (2002). Nat. Med., 8, 979–986.

  • Williams EE, Trout LJ, Gallo RM, Pitfield SE, Bryant I, Penington DJ and Riese II DJ . (2003). Cancer Lett., 192, 67–74.

  • Wilson KS, Roberts H, Leek R, Harris AL and Geradts J . (2002). Am. J. Pathol., 161, 1171–1185.

  • Witton CJ, Reeves JR, Going JJ, Cooke TG and Bartlett JM . (2003). J. Pathol., 200, 290–297.

    Article  CAS  Google Scholar 

  • Yarden Y and Sliwkowski MX . (2001). Nat. Rev. Mol. Cell Biol., 2, 127–137.

  • Yip SS, Crew AJ, Gee JM, Hui R, Blamey RW, Robertson JF, Nicholson RI, Sutherland RL and Daly RJ . (2000). Int. J. Cancer, 88, 363–368.

    Article  CAS  Google Scholar 

  • Zhou W and Carpenter G . (2002). Inflamm. Res., 51, 91–101.

Download references

Acknowledgements

This work was supported by US Public Health Service Grant R01CA80065 from the National Cancer Institute.

Author information

Author notes

  1. Dhara N Amin

    Present address: Department of Surgical Research, Childrens Hospital, Boston, MA, 02115

Authors and Affiliations

  1. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, 06510, CT, USA

    Dhara N Amin

  2. Department of Pathology, Yale University School of Medicine, New Haven, 06520-8023, PO Box 208023, CT, USA

    Dhara N Amin, Archibald S Perkins & David F Stern

Authors
  1. Dhara N Amin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Archibald S Perkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David F Stern
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David F Stern.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Amin, D., Perkins, A. & Stern, D. Gene expression profiling of ErbB receptor and ligand-dependent transcription. Oncogene 23, 1428–1438 (2004). https://doi.org/10.1038/sj.onc.1207257

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207257

Keywords

This article is cited by

Search

Advanced search

Quick links