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:

Estrogen regulation of vascular endothelial growth factor gene expression in ZR-75 breast cancer cells through interaction of estrogen receptor α and SP proteins

Oncogene volume 23, pages 1052–1063 (2004)Cite this article

Abstract

Vascular endothelial growth factor (VEGF) is expressed in multiple hormone-dependent cancer cells/tumors. Treatment of ZR-75 breast cancer cells with 17β-estradiol (E2) induced a greater than fourfold increase of VEGF mRNA levels. ZR-75 breast cancer cells were transfected with pVEGF1, a construct containing a −2018 to +50 VEGF promoter insert, and E2 induced reporter gene (luciferase) activity. Deletion and mutation analysis of the VEGF gene promoter identified a GC-rich region (−66 to −47) which was required for E2-induced transactivation of pVEGF5, a construct containing the minimal promoter (−66 to +54) that exhibited E2-responsiveness. Interactions of nuclear proteins from ZR-75 cells with the proximal GC-rich region of the VEGF gene promoter were investigated by electrophoretic mobility shift and chromatin immunoprecipitation assays. The results demonstrate that both Sp1 and Sp3 proteins bound the GC-rich motif (−66 to −47), and estrogen receptor α (ERα) interactions were confirmed by chromatin immunoprecipitation. Moreover, E2-dependent activation of constructs containing proximal and distal GC/GT-rich regions of the VEGF promoter was inhibited in ZR-75 cells transfected with small inhibitory RNAs for Sp1 and Sp3. These results were consistent with a mechanism of hormone activation of VEGF through ERα/Sp1 and ERα/Sp3 interactions with GC-rich motifs.

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

Similar content being viewed by others

References

  • Abdelrahim M, Samudio I, Smith R, Burghardt R and Safe S . (2002). J. Biol. Chem., 277, 28815–28822.

  • Augereau P, Miralles F, Cavailles V, Gaudelet C, Parker M and Rochefort H . (1994). Mol. Endocrinol., 8, 693–703.

  • Bae DG, Gho YS, Yoon WH and Chae CB . (2000). J. Biol. Chem., 275, 13588–13596.

  • Berry M, Nunez A-M and Chambon P . (1989). Proc. Natl. Acad. Sci. USA, 86, 1218–1222.

  • Bogin L and Degani H . (2002). Cancer Res., 62, 1948–1951.

  • Boocock CA, Charnock-Jones DS, Sharkey AM, McLaren J, Barker PJ, Wright KA, Twentyman PR and Smith SK . (1995). J. Natl. Cancer Inst., 87, 506–516.

  • Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, Abeloff MD, Simons JW, van Diest PJ and van der Wall E . (2001). J. Natl. Cancer Inst., 93, 309–314.

  • Brekken RA, Overholser JP, Stastny VA, Waltenberger J, Minna JD and Thorpe PE . (2000). Cancer Res., 60, 5117–5124.

  • Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Dvorak HF and Senger DR . (1993). Am. J. Pathol., 143, 1255–1262.

  • Buteau-Lozano H, Ancelin M, Lardeux B, Milanini J and Perrot-Applanat M . (2002). Cancer Res., 62, 4977–4984.

  • Castro-Rivera E, Samudio I and Safe S . (2001). J. Biol. Chem., 276, 30853–30861.

  • Cavailles V, Augereau P and Rochefort H . (1993). Proc. Natl. Acad. Sci. USA, 90, 203–207.

  • Cavailles V, Garcia M and Rochefort H . (1989). Mol. Endocrinol., 3, 552–558.

  • Classen-Linke I, Alfer J, Krusche CA, Chwalisz K, Rath W and Beier HM . (2000). Steroids, 65, 763–771.

  • Cullinan-Bove K and Koos RD . (1993). Endocrinology, 133, 829–837.

  • DiRenzo J, Shang Y, Phelan M, Sif S, Myers M, Kingston R and Brown M . (2000). Mol. Cell. Biol., 20, 7541–7549.

  • Duan R, Porter W and Safe S . (1998). Endocrinology, 139, 1981–1990.

  • Enholm B, Paavonen K, Ristimaki A, Kumar V, Gunji Y, Klefstrom J, Kivinen L, Laiho M, Olofsson B, Joukov V, Eriksson U and Alitalo K . (1997). Oncogene, 14, 2475–2483.

  • Ferrara N and Davis-Smyth T . (1997). Endocr. Rev., 18, 4–25.

  • Finkenzeller G, Sparacio A, Technau A, Marme D and Siemeister G . (1997). Oncogene, 15, 669–676.

  • Gille J, Swerlick RA and Caughman SW . (1997). EMBO J., 16, 750–759.

  • Gille J, Swerlick RA, Lawley TJ and Caughman SW . (1996). Blood, 87, 211–217.

  • Gillesby B, Santostefano M, Porter W, Wu ZF, Safe S and Zacharewski T . (1997). Biochemistry, 36, 6080–6089.

  • Goldman CK, Kim J, Wong WL, King V, Brock T and Gillespie GY . (1993). Mol. Biol. Cell, 4, 121–133.

  • Hanahan D and Folkman J . (1996). Cell, 86, 353–364.

  • Harborth J, Elbashir SM, Bechert K, Tuschl T and Weber K . (2001). J. Cell Sci., 114, 4557–4565.

  • Hyder SM, Chiappetta C and Stancel GM . (1997). Cancer Lett., 120, 165–171.

  • Hyder SM, Murthy L and Stancel GM . (1998). Cancer Res., 58, 392–395.

  • Hyder SM, Nawaz Z, Chiappetta C and Stancel GM . (2000). Cancer Res., 60, 3183–3190.

  • Hyder SM, Stancel GM, Chiappetta C, Murthy L, Boettger-Tong HL and Makela S . (1996). Cancer Res., 56, 3954–3960.

  • Kimura H, Weisz A, Ogura T, Hitomi Y, Kurashima Y, Hashimoto K, D'Acquisto F, Makuuchi M and Esumi H . (2001). J. Biol. Chem., 276, 2292–2298.

  • Klotz DM, Castles CG, Fuqua SAW, Spriggs LL and Hill SM . (1995). Biochem. Biophys. Res. Commun., 210, 609–615.

  • Laitinen M, Ristimaki A, Honkasalo M, Narko K, Paavonen K and Ritvos O . (1997). Endocrinology, 138, 4748–4756.

  • Linderholm BK, Lindahl T, Holmberg L, Klaar S, Lennerstrand J, Henriksson R and Bergh J . (2001). Cancer Res., 61, 2256–2260.

  • Monte D, DeWitte F and Hum DW . (1998). J. Biol. Chem., 273, 4585–4591.

  • Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leitman DC and Taylor RN . (2000). Proc. Natl. Acad. Sci. USA, 97, 10972–10977.

  • Nakamura J, Savinov A, Lu Q and Brodie A . (1996). Endocrinology, 137, 5589–5596.

  • Owen GI, Richer JK, Tung L, Takimoto G and Horwitz KB . (1998). J. Biol. Chem., 273, 10696–10701.

  • Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ and Scanlan TS . (1997). Science, 277, 1508–1510.

  • Pal S, Claffey KP, Cohen HT and Mukhopadhyay D . (1998). J. Biol. Chem., 273, 26277–26280.

  • Pepper MS, Ferrara N, Orci L and Montesano R . (1992). Biochem. Biophys. Res. Commun., 189, 824–831.

  • Pipaón C, Tsai SY and Tsai MJ . (1999). Mol. Cell. Biol., 19, 2734–2745.

  • Porter W, Saville B, Hoivik D and Safe S . (1997). Mol. Endocrinol., 11, 1569–1580.

  • Rohr O, Aunis D and Schaeffer E . (1997). J. Biol. Chem., 272, 31149–31155.

  • Ruohola JK, Valve EM, Karkkainen MJ, Joukov V, Alitalo K and Härkönen PL . (1999). Mol. Cell. Endocrinol., 149, 29–40.

  • Ryuto M, Ono M, Izumi H, Yoshida S, Weich HA, Kohno K and Kuwano M . (1996). J. Biol. Chem., 271, 28220–28228.

  • Safe S . (2001). Vitam. Horm., 62, 231–252.

  • Salimath B, Marme D and Finkenzeller G . (2000). Oncogene, 19, 3470–3476.

  • Samudio I, Vyhlidal C, Wang F, Stoner M, Chen I, Kladde M, Barhoumi R, Burghardt R and Safe S . (2001). Endocrinology, 142, 1000–1008.

  • Sathya G, Li W, Klinge CM, Anolik JH, Hilf R and Bambara RA . (1997). Mol. Endocrinol., 11, 1994–2003.

  • Saville B, Wormke M, Wang F, Nguyen T, Enmark E, Kuiper G, Gustafsson J-A and Safe S . (2000). J. Biol. Chem., 275, 5379–5387.

  • Scheidegger KJ, Cenni B, Picard D and Delafontaine P . (2000). J. Biol. Chem., 275, 38921–38928.

  • Schlaeppi JM and Wood JM . (1999). Cancer Metastasis Rev., 18, 473–481.

  • Shi Q, Le X, Abbruzzese JL, Peng Z, Qian CN, Tang H, Xiong Q, Wang B, Li XC and Xie K . (2001). Cancer Res., 61, 4143–4154.

  • Simmen RCM, Chung TE, Imataka H, Michel FJ, Badinga L and Simmen FA . (1999). Endocrinology, 140, 2517–2525.

  • Stoner M, Wang F, Wormke M, Nguyen T, Samudio I, Vyhlidal C, Marme D, Finkenzeller G and Safe S . (2000). J. Biol. Chem., 275, 22769–22779.

  • Suzuki Y, Shimada J, Shudo K, Matsumura M, Crippa MP and Kojima S . (1999). Blood, 93, 4264–4276.

  • Viglietto G, Maglione D, Rambaldi M, Cerutti J, Romano A, Trapasso F, Fedele M, Ippolito P, Chiappetta G and Botti G . (1995). Oncogene, 11, 1569–1579.

  • Weisz A and Rosales R . (1990). Nucleic Acids Res., 18, 5097–5106.

  • Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R and Safe S . (2003). Mol. Cell. Biol., 23, 1843–1855.

  • Xiao H, Hasegawa T and Isobe K-I . (2000). J. Biol. Chem., 275, 1371–1376.

  • Yoshiji H, Harris SR and Thorgeirsson UP . (1997). Cancer Res., 57, 3924–3928.

  • Zetter BR . (1998). Annu. Rev. Med., 49, 407–424.

Download references

Acknowledgements

Supported by financial assistance from the National Institutes of Health (ES04176, CA076636 and ES09106) and the Texas Agricultural Experiment Station.

Author information

Authors and Affiliations

  1. Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, 77843-4466, TX, USA

    Matthew Stoner, Mark Wormke, Ismael Samudio, Chunhua Qin, Maen Abdelrahim & Stephen Safe

  2. Department of Biochemistry and Biophysics, Texas A&M University, College Station, 77843-4466, TX, USA

    Brad Saville

Authors
  1. Matthew Stoner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark Wormke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brad Saville
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ismael Samudio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chunhua Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maen Abdelrahim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stephen Safe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen Safe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stoner, M., Wormke, M., Saville, B. et al. Estrogen regulation of vascular endothelial growth factor gene expression in ZR-75 breast cancer cells through interaction of estrogen receptor α and SP proteins. Oncogene 23, 1052–1063 (2004). https://doi.org/10.1038/sj.onc.1207201

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207201

Keywords

This article is cited by

Search

Advanced search

Quick links