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 Article
  • Published:

Progestin-induced caveolin-1 expression mediates breast cancer cell proliferation

Abstract

Progestin regulation of gene expression was assessed in the progestin-dependent murine tumor line C4HD which requires MPA, a synthetic progestin, for in vivo growth and expresses high levels of progesterone receptor (PR). By using suppressive subtractive hybridization, caveolin-1 was identified as a gene whose expression was increased with in vivo MPA treatment. By Northern and Western blot analysis, we further confirmed that caveolin-1 mRNA and protein expression increased in MPA-treated tumors as compared with untreated tumors. When primary cultures of C4HD cells were treated in vitro with MPA, caveolin-1 levels also increased, effect that was abolished by pre-treatment with progestin antagonist RU486. In addition, MPA promoted strong caveolin-1 promoter transcriptional activation both in mouse and human breast cancer cells. We also showed that MPA regulation of caveolin-1 expression involved in activation of two signaling pathways: MAPK and PI-3K. Short-term MPA treatment of C4HD cells led to tyrosine phosphorylation of caveolin-1 protein, where Src was the kinase involved. Additionally, we showed that MPA-induced association of caveolin-1 and PR, which was detected by coimmunoprecipitation and by confocal microscopy. Finally, we proved that MPA-induced proliferation of C4HD cells was inhibited by suppression of caveolin-1 expression with antisense oligodeoxynucleotides to caveolin-1 mRNA. Furthermore, we observed that inhibition of caveolin-1 expression abrogated PR capacity to induced luciferase activity from a progesterone response element-driven reporter plasmid. Comprehensively, our results demonstrated for the first time that caveolin-1 expression is upregulated by progestin in breast cancer. We also demonstrated that caveolin-1 is a downstream effector of MPA that is partially responsible for the stimulation of growth of breast cancer 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

Similar content being viewed by others

References

  • Anderson RG . (1998). Annu Rev Biochem 67: 199–225.

  • Balana ME, Labriola L, Salatino M, Movsichoff F, Peters G, Charreau EH et al. (2001). Oncogene 20: 34–47.

  • Balana ME, Lupu R, Labriola L, Charreau EH, Elizalde PV . (1999). Oncogene 18: 6370–6379.

  • Ballare C, Uhrig M, Bechtold T, Sancho E, Di Domenico M, Migliaccio A et al. (2003). Mol Cell Biol 23: 1994–2008.

  • Boonyaratanakornkit V, Scott MP, Ribon V, Sherman L, Anderson SM, Maller JL et al. (2001). Mol Cell 8: 269–280.

  • Castoria G, Barone MV, Di Domenico M, Bilancio A, Ametrano D, Migliaccio A et al. (1999). EMBO J 18: 2500–2510.

  • Cho KA, Ryu SJ, Park JS, Jang IS, Ahn JS, Kim KT et al. (2003). J Biol Chem 278: 27789–27795.

  • Couet J, Sargiacomo M, Lisanti MP . (1997). J Biol Chem 272: 30429–30438.

  • Diatchenko L, Lau YF, Campbell AP, Chenchik A, Moqadam F, Huang B et al. (1996). Proc Natl Acad Sci USA 93: 6025–6030.

  • Engelman JA, Lee RJ, Karnezis A, Bearss DJ, Webster M, Siegel P et al. (1998). J Biol Chem 273: 20448–20455.

  • Engelman JA, Wykoff CC, Yasuhara S, Song KS, Okamoto T, Lisanti MP . (1997). J Biol Chem 272: 16374–16381.

  • Engelman JA, Zhang XL, Razani B, Pestell RG, Lisanti MP . (1999). J Biol Chem 274: 32333–32341.

  • Elizalde PV, Lanari C, Molinolo AA, Guerra FK, Balana ME, Simian M et al. (1998). J Steroid Biochem Mol Biol 67: 305–317.

  • Galbiati F, Razani B, Lisanti MP . (2001). Trends Mol Med 7: 435–441.

  • Glenney Jr JR . (1989). J Biol Chem 264: 20163–20166.

  • Glenney Jr JR . (1992). FEBS Lett 314: 45–48.

  • Hayashi K, Matsuda S, Machida K, Yamamoto T, Fukuda Y, Nimura Y et al. (2001). Cancer Res 61: 2361–2364.

  • Ho SM . (2003). Reprod Biol Endocrinol 1: 73.

  • Hurlstone AF, Reid G, Reeves JR, Fraser J, Strathdee G, Rahilly M et al. (1999). Oncogene 18: 1881–1890.

  • Ismail PM, Amato P, Soyal SM, DeMayo FJ, Conneely OM, O'Malley BW et al. (2003). Steroids 68: 779–787.

  • Kiss AL, Turi A, Mullner N, Kovacs E, Botos E, Greger A . (2005). Mol Cell Endocrinol 245: 128–137.

  • Kogo H, Fujimoto T . (2000). FEBS Lett 465: 119–123.

  • Koleske AJ, Baltimore D, Lisanti MP . (1995). Proc Natl Acad Sci USA 92: 1381–1385.

  • Kordon E, Lanari C, Meiss R, Elizalde P, Charreau E, Dosne PC . (1990). Breast Cancer Res Treat 17: 33–43.

  • Labriola L, Salatino M, Proietti CJ, Pecci A, Coso OA, Kornblihtt AR et al. (2003). Mol Cell Biol 23: 1095–1111.

  • Lange CA, Richer JK, Horwitz KB . (1999). Mol Endocrinol 13: 829–836.

  • Lange CA, Richer JK, Shen T, Horwitz KB . (1998). J Biol Chem 273: 31308–31316.

  • Lee H, Park DS, Razani B, Russell RG, Pestell RG, Lisanti MP . (2002). Am J Pathol 161: 1357–1369.

  • Lee H, Volonte D, Galbiati F, Iyengar P, Lublin DM, Bregman DB et al. (2000). Mol Endocrinol 14: 1750–1775.

  • Li L, Ren CH, Tahir SA, Ren C, Thompson TC . (2003). Mol Cell Biol 23: 9389–9404.

  • Li L, Yang G, Ebara S, Satoh T, Nasu Y, Timme TL et al. (2001). Cancer Res 61: 4386–4392.

  • Li S, Seitz R, Lisanti MP . (1996). J Biol Chem 271: 3863–3868.

  • Lu ML, Schneider MC, Zheng Y, Zhang X, Richie JP . (2001). J Biol Chem 276: 13442–13451.

  • Lydon JP, Sivaraman L, Conneely OM . (2000). J Mammary Gland Biol Neoplasia 5: 325–338.

  • Magnusson C, Baron JA, Correia N, Bergstrom R, Adami HO, Persson I . (1999). Int J Cancer 81: 339–344.

  • Migliaccio A, Piccolo D, Castoria G, Di Domenico M, Bilancio A, Lombardi M et al. (1998). EMBO J 17: 2008–2018.

  • Montecchia MF, Lamb C, Molinolo AA, Luthy IA, Pazos P, Charreau E et al. (1999). J Steroid Biochem Mol Biol 68: 11–21.

  • Mouraviev V, Li L, Tahir SA, Yang G, Timme TM, Goltsov A et al. (2002). J Urol 168: 1589–1596.

  • Nasu Y, Timme TL, Yang G, Bangma CH, Li L, Ren C et al. (1998). Nat Med 4: 1062–1064.

  • Pflug BR, Reiter RE, Nelson JB . (1999). Prostate 40: 269–273.

  • Proietti C, Salatino M, Rosemblit C, Carnevale R, Pecci A, Kornblihtt AR et al. (2005). Mol Cell Biol 25: 4826–4840.

  • Puricelli L, Proietti CJ, Labriola L, Salatino M, Balana ME, Aguirre GJ et al. (2002). Int J Cancer 100: 642–653.

  • Razandi M, Oh P, Pedram A, Schnitzer J, Levin ER . (2002). Mol Endocrinol 16: 100–115.

  • Razani B, Woodman SE, Lisanti MP . (2002). Pharmacol Rev 54: 431–467.

  • Ross RK, Paganini-Hill A, Wan PC, Pike MC . (2000). J Natl Cancer Inst 92: 328–332.

  • Salatino M, Schillaci R, Proietti CJ, Carnevale R, Frahm I, Molinolo AA et al. (2004). Oncogene 23: 5161–5174.

  • Scherer PE, Okamoto T, Chun M, Nishimoto I, Lodish HF, Lisanti MP . (1996). Proc Natl Acad Sci USA 93: 131–135.

  • Scherer PE, Tang Z, Chun M, Sargiacomo M, Lodish HF, Lisanti MP . (1995). J Biol Chem 270: 16395–16401.

  • Schlegel A, Wang C, Katzenellenbogen BS, Pestell RG, Lisanti MP . (1999). J Biol Chem 274: 33551–33556.

  • Schlegel A, Wang C, Pestell RG, Lisanti MP . (2001). Biochem J 359: 203–210.

  • Shaul PW, Anderson RG . (1998). Am J Physiol 275: L843–L851.

  • Sloan EK, Stanley KL, Anderson RL . (2004). Oncogene 23: 7893–7897.

  • Smart EJ, Graf GA, McNiven MA, Sessa WC, Engelman JA, Scherer PE et al. (1999). Mol Cell Biol 19: 7289–7304.

  • Syed V, Mukherjee K, Lyons-Weiler J, Lau KM, Mashima T, Tsuruo T et al. (2005). Oncogene 24: 1774–1787.

  • Tahir SA, Yang G, Ebara S, Timme TL, Satoh T, Li L et al. (2001). Cancer Res 61: 3882–3885.

  • Thompson TC, Timme TL, Li L, Goltsov A . (1999). Apoptosis 4: 233–237.

  • Timme TL, Satoh T, Tahir SA, Wang H, Teh BS, Butler EB et al. (2003). Curr Drug Targets 4: 251–261.

  • Trouet D, Nilius B, Jacobs A, Remacle C, Droogmans G, Eggermont J . (1999). J Physiol (London) 520: 113–119.

  • Volonte D, Galbiati F, Pestell RG, Lisanti MP . (2001). J Biol Chem 276: 8094–8103.

  • Watson CS, Gametchu B . (2003). Exp Biol Med 228: 1272–1281.

  • Way M, Parton RG . (1996). FEBS Lett 378: 108–112.

  • Williams TM, Hassan GS, Li J, Cohen AW, Medina F, Frank PG et al. (2005). J Biol Chem 280: 25134–25145.

  • Williams TM, Medina F, Badano I, Hazan RB, Hutchinson J, Muller WJ et al. (2004). J Biol Chem 279: 51630–51646.

  • Yamamoto M, Toya Y, Schwencke C, Lisanti MP, Myers Jr MG, Ishikawa Y . (1998). J Biol Chem 273: 26962–26968.

  • Yang G, Addai J, Ittmann M, Wheeler TM, Thompson TC . (2000). Clin Cancer Res 6: 3430–3433.

  • Yang G, Truong LD, Timme TL, Ren C, Wheeler TM, Park SH et al. (1998). Clin Cancer Res 4: 1873–1880.

  • Yang G, Truong LD, Wheeler TM, Thompson TC . (1999). Cancer Res 59: 5719–5723.

Download references

Acknowledgements

We are grateful to Dr Alfredo Molinolo for his continuous assistance, Dr Adali Pecci for help with the manuscript revision and Dr Liliana Dain for her assistance with the caveolin mutational analysis. We also thank N Lope for her expert assistance with animal care, Laboratorios Gador for providing Medrosterona and C Lanari for providing the MPA-induced mammary tumor model. This work was supported by the following grants: Centro Argentino Brasileño de Biotecnología, IDB 1201/OC-AR PICT 2002 05-11055 and PICT 05-06324 from the National Agency of Scientific Promotion of Argentina; Oncomed-Reno CONICET 1819/03, from the Henry Moore Institute of Argentina; Fundación Fiorini and CONICET PIP 2263/2000.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P V Elizalde.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Salatino, M., Beguelin, W., Peters, M. et al. Progestin-induced caveolin-1 expression mediates breast cancer cell proliferation. Oncogene 25, 7723–7739 (2006). https://doi.org/10.1038/sj.onc.1209757

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209757

Keywords

This article is cited by

Search

Quick links