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  • Original Paper
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Estrogen receptor regulates the degradation of insulin receptor substrates 1 and 2 in breast cancer cells

Abstract

In breast cancer cells, 17-β-estradiol (E2) upregulates the expression of insulin receptor substrate 1 (IRS-1), a molecule transmitting insulin-like growth factor-I (IGF-I) signals through the PI-3K/Akt survival pathways. The stimulation of IRS-1 by E2 has been documented on the transcriptional level. Here we studied whether the expression of estrogen receptor (ER)-α affects IRS molecules post-transcriptionally. We used ER-α-negative MDA-MB-231 breast cancer cells and MDA-MB-231 cells with re-expressed ER-α. In MDA-MB-231 cells cultured under serum-free conditions, IRS-1 and IRS-2 were degraded through the 26S proteasome and calpain pathways. Re-expression of ER-α in MDA-MB-231 cells correlated with enhanced stability of IRS molecules. This effect coincided with significantly reduced ubiquitination of IRS-1 and IRS-2, but did not involve increased IRS-1 and IRS-2 transcription. The interference of ER-α with IRS-1 and IRS-2 turnover could rely on the competition for common degradation pathways, as in MDA-MB-231/ER cells, ER-α processing was blocked by proteasome and calpain inhibitors. Notably, a fraction of the cytosolic ER-α colocalized and coprecipitated with IRS-1 and IRS-2, indicating a possible common destination for these proteins. The stabilization of IRS-1 in MDA-MB-231/ER cells was paralleled by the upregulation of the IRS-1/Akt/GSK-3 pathway and improved survival in the presence of IGF-I, whereas IRS-2 was not involved in IGF-I signaling.

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References

  • Aberle H, Bauer A, Stappert J, Kispert A and Kemler R . (1997). EMBO J., 16, 3797–3804.

  • Aguirre V and White M . (2000). Curr. Opin. Endocrin. Diab., 7, 1–7.

  • Araki E, Sun XJ, Haag III BL, Chuang LM, Zhang Y, Yang-Feng TL, White MF and Kahn CR . (1993). Diabetes, 42, 1041–1054.

  • Ashok BT, Kim E, Mittelman A and Tiwari RK . (2001). Int. J. Mol. Med., 8, 385–390.

  • Bartucci M, Morelli C, Mauro L, Ando' S and Surmacz E . (2001). Cancer Res., 61, 6747–6754.

  • Bergmann U, Funatomi H, Kornmann M, Beger HG and Korc M . (1996). Biochem. Biophys. Res. Commun., 220, 886–890.

  • Burks DJ and White MF . (2001). Diabetes, 50, S140–S145.

  • Ducluzeau PH, Perretti N, Laville M, Andreelli F, Vega N, Riou JP and Vidal H . (2001). Diabetes, 50, 1134–1142.

  • Dupont J, Derouet M, Simon J and Taouis M . (1999). J. Endocrinol., 162, 67–76.

  • Fasshauer M, Klein J, Kriauciunas KM, Ueki K, Benito M and Kahn CR . (2001). Mol. Cell. Biol., 21, 319–329.

  • Giovannone B, Scaldaferri ML, Federici M, Porzio O, Lauro D, Fusco A, Sbraccia P, Borboni P, Lauro R and Sesti G . (2000). Diabetes Metab. Res. Rev., 16, 434–441.

  • Guvakova MA and Surmacz E . (1997). Cancer Res., 57, 2606–2610.

  • Jackson JG, White MF and Yee D . (1998). J. Biol. Chem., 273, 9994–10003.

  • Jackson JG, Zhang X, Yoneda T and Yee D . (2001). Oncogene, 20, 7318–7325.

  • Joazeiro CAP and Hunter T . (2000). Science, 289, 2061–2062.

  • Kahlert S, Nuedling S, Van Eickels M, Vetter H, Meyer R and Grohe' C . (2000) J. Biol. Chem., 275, 18447–18453.

  • Kornmann M, Maruyama H, Bergmann U, Tangvoranuntakul P, Beger HG, White MF and Korc M . (1998). Cancer Res., 58, 4250–4254.

  • Lassak A, Del Valle L, Peruzzi F, Wang JY, Enam S, Croul S, Khalili K and Reiss K . (2002). J. Biol. Chem., 277, 17231–17238.

  • Lee AV, Gooch JL, Oesterreich S, Guler RL and Yee D . (2000). Mol. Cell. Biol., 20, 1489–1496.

  • Lee AV, Jackson JG, Gooch JL, Hilsenbeck SG, Coronado-Heinsohn E, Osborne CK and Yee D . (1999). Mol. Endocrinol., 13, 787–796.

  • Lonard DM, Nawaz Z, Smith CL and O'Malley BW . (2000). Mol. Cell., 5, 939–948.

  • Mauro L, Salerno M, Panno ML, Bellizzi D, Sisci D, Miglietta A, Surmacz E and Ando' S . (2001). Biochem. Biophys. Res. Commun., 288, 685–689.

  • Molloy CA, May FE and Westley BR (2000). J. Biol. Chem., 275, 12565–12571.

  • Murayama A, Fukai F and Murachi T . (1984). J. Biochem., 95, 1697–1704.

  • Nawaz Z, Lonard DM, Dennis A, Smith CL and O'Malley BW . (1999). Proc. Natl. Acad. Sci. USA, 96, 1858–1862.

  • Pederson TM, Kramer DL and Rondinone CM (2001). Diabetes, 50, 24–31.

  • Powzaniuk MA, Trotta R, Loza MJ, Harth A, Iozzo RV, Eisenlohr LC, Perussia B and Calabretta B . (2001). J. Immunol., 167, 242–249.

  • Prisco M, Santini F, Baffa R, Liu M, Drakas R, Wu A and Baserga R . (2002). J. Biol. Chem., 277, 32078–32085.

  • Rice KM, Turnbow MA and Gamer CW . (1993). Biochem. Biophys. Res. Commun., 190, 961–197.

  • Richards GR, Klotz DM, Bush MR, Walmer DK and DiAugustine RP . (2001). Endocrinology, 142, 3842–3849.

  • Rommel C, Clarke BA, Zimmermann S, Nunez L, Rossman R, Reid K, Moelling K, Yancopoulos GD and Glass DJ . (1999). Science, 286, 1738–1740.

  • Rui L, Fisher TL, Thomas J and White MF . (2001). J. Biol. Chem., 276, 40362–40367.

  • Sachdev D and Yee D . (2001). Endocr. Relat. Cancer, 8, 197–209.

  • Sakoda H, Ogihara T, Anai M, Funaki M, Inukai K, Katagiri H, Fukushima Y, Onishi Y, Ono H, Fujishiro M, Kikuchi M, Oka Y and Asano T . (2000). Diabetes, 49, 1700–1708.

  • Salerno M, Sisci D, Mauro L, Guvakova MA, Ando S and Surmacz E . (1999). Int. J. Cancer, 81, 299–304.

  • Sasaki Y, Zhang XF, Nishiyama M, Avruch J and Wands JR . (1993). J. Biol. Chem., 268, 3805–3808.

  • Shaw LM . (2001). Mol. Cell. Biol., 21, 5082–5093.

  • Shepherd PR, Withers D and Siddle K . (1998). Biochem. J., 333, 471–490.

  • Shiba E, Shoushin K, Fujitani M, Kambayashi J, Kawamura I, Tsujimoto S, Shimomura K, Tanji Y, Taguchi T, Kimoto Y, Izukura M and Takai S . (1996). Anticancer Res., 16, 773–778.

  • Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW and Liao JK . (2000). Nature, 407, 538–541.

  • Smith LK, Bradshaw M, Croall DE and Garner CW . (1993). Biochem. Biophys. Res. Commun., 196, 767–772.

  • Smith LK, Rice KM and Garner CW . (1996). Mol. Cell. Endocrinol., 30, 81–92.

  • Smith U, Gogg S, Johansson A, Olausson T, Rotter V and Svalstedt B . (2001). FASEB J., 15, 215–220.

  • Song RX, McPherson RA, Adam L, Bao Y, Shupnik M, Kumar R and Santen RJ . (2002). Mol. Endocrinol., 16, 116–127.

  • Spector SA, Olson ET, Gumbs AA, Friess H, Buchler MW and Seymour NE . (1999). J. Surg. Res., 83, 32–35.

  • Sun M, Paciga JE, Feldman RI, Yuan Z, Coppola D, Lu YY, Shelley SA, Nicosia SV and Cheng JQ . (2001). Cancer Res., 61, 5985–5991.

  • Sun XJ, Goldberg JL, Qiao L and Mitchell JJ . (1999). Diabetes, 48, 1359–1364.

  • Surmacz E . (2000). J. Mammary Gland Biol. Neoplasia, 5, 95–105.

  • Turnbow MA, Keller SR, Rice KM and Garner CW . (1994). J. Biol. Chem., 269, 2516–2520.

  • Vassen L, Wegrzyn W and Klein-Hitpass L . (1999). Mol. Endocrinol., 13, 485–494.

  • Yenush L and White MF . (1997). BioEssays, 19, 491–500.

  • Zhang H, Hoff H and Sell C . (2000). J. Biol. Chem., 275, 22558–22562.

  • Zhang J, Ou J, Bashmakov Y, Horton JD, Brown MS and, Goldstein JL . (2001). Proc. Natl. Acad. Sci. USA, 27, 3756–3761.

  • Zimmermann S and Moelling K . (1999). Science, 286, 1741–1744.

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Acknowledgements

This work was supported by the US Department of Defense Breast Cancer Research Program Grants DAMD17-99-1-9407 and DAMD 17-97-1-7211, and by the American–Italian Cancer Foundation.

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Correspondence to Eva Surmacz.

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Morelli, C., Garofalo, C., Bartucci, M. et al. Estrogen receptor regulates the degradation of insulin receptor substrates 1 and 2 in breast cancer cells. Oncogene 22, 4007–4016 (2003). https://doi.org/10.1038/sj.onc.1206436

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