Abstract
Insulin receptor substrate 1 (IRS-1) is a major signaling molecule activated by the insulin and insulin-like growth factor I receptors. Recent data obtained in different cell models suggested that in addition to its conventional role as a cytoplasmic signal transducer, IRS-1 has a function in the nuclear compartment. However, the role of nuclear IRS-1 in breast cancer has never been addressed. Here we report that in estrogen receptor α (ERα)-positive MCF-7 cells, (1) a fraction of IRS-1 was translocated to the nucleus upon 17-β-estradiol (E2) treatment; (2) E2-dependent nuclear translocation of IRS-1 was blocked with the antiestrogen ICI 182,780; (3) nuclear IRS-1 colocalized and co-precipitated with ERα; (4) the IRS-1:ERα complex was recruited to the E2-sensitive pS2 gene promoter. Notably, IRS-1 interaction with the pS2 promoter did not occur in ERα-negative MDA-MB-231 cells, but was observed in MDA-MB-231 cells retransfected with ERα. Transcription reporter assays with E2-sensitive promoters suggested that the presence of IRS-1 inhibits ERα activity at estrogen-responsive element-containing DNA. In summary, our data suggested that nuclear IRS-1 interacts with ERα and that this interaction might influence ERα transcriptional activity.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ando S, Panno ML, Salerno M, Sisci D, Mauro L, Lanzino M and Surmacz E . (1998). Biochem. Biophys. Res. Commun., 253, 315–319.
Bartucci M, Morelli C, Mauro L, Ando' S and Surmacz E . (2001). Cancer Res., 61, 6747–6754.
Boylan JM and Gruppuso PA . (2002). Endocrinology, 143, 4178–4183.
Burks DJ and White MF . (2001). Diabetes, 50, S140–S145.
Chan TW, Pollak M and Huynh H . (2001). Clin. Cancer Res., 7, 2545–2554.
Guvakova MA and Surmacz E . (1997). Cancer Res., 57, 2606–2610.
Kahlert S, Nuedling S, van Eickels M, Vetter H, Meyer R and Grohe' C . (2000). J. Biol. Chem., 275, 18447–18453.
Lannigan DA . (2003). Steroids, 68, 1–9.
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, Jackson JG, Gooch JL, Hilsenbeck SG, Coronado-Heinsohn E, Osborne CK and Yee D . (1999). Mol. Endocrinol., 10, 787–796.
Maggiolini M, Bonofiglio D, Marsico S, Panno ML, Cenni B, Picard D and Andò S . (2001). Mol. Pharmacol., 60, 595–602.
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.
Metiver R, Stark A, Flouriot G, Hubner MR, Brand H, Penot G, Manu D, Denger S, Reid G, Kos M, Russel RB, Kah O, Pakdel F and Gannon F . (2002). Mol. Cell, 10, 1019–1032.
Molloy CA, May FEB and Westley BR . (2000). J. Biol. Chem., 275, 12565–12571.
Morelli C, Garofalo C, Bartucci M and Surmacz E . (2003). Oncogene, 22, 4007–4016.
Prisco M, Santini F, Baffa R, Liu M, Drakas R, Wu A and Baserga R . (2002). J. Biol. Chem., 277, 32078–32085.
Reid G, Hubner M R, Metivier R, Brand H, Denger S, Manu D, Beaudouin J, Ellenberg J and Gannon F . (2003). Mol. Cell, 11, 695–707.
Sachdev D and Yee D . (2001). Endocr. Relat. Cancer, 8, 197–209.
Salerno M, Sisci D, Mauro L, Guvakova M, Ando S and Surmacz E . (1999). Int. J. Cancer, 81, 299–304.
Schnarr B, Strunz K, Ohsam J, Benner A, Wacker J and Mayer D . (2000). Int. J. Cancer, 89, 506–513.
Sciacca L, Prisco M, Wu A, Belfiore A, Vigneri R and Baserga R . (2003). Endocrinology, 144, 2650–2658.
Seol KC and Kim SJ . (2003). Biochem. Biophys. Res. Commun., 306, 898–904.
Shang Y, Hu X, DiRenzo J, Lazar MA and Brown M . (2000). Cell, 103, 843–852.
Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW and Liao JK . (2000). Nature, 407, 538–541.
Song R, Mcpherson RA, Adam L, Bao Y, Shupnik M, Kumar R and Santen RJ . (2002). Mol. Endocrinol., 16, 116–127.
Sun H, Tu X, Prisco M, Wu A, Casaburi I and Baserga R . (2003). Mol. Endocrinol., 17, 472–486.
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.
Surmacz E . (2000). J. Mammary Gland Biol. Neopl., 5, 95–105.
Surmacz E and Burgaud JL . (1995). Clin. Cancer Res., 1, 1429–1436.
Tu X, Batta P, Innocent N, Prisco M, Casaburi I, Belletti B and Baserga R . (2002). J. Biol. Chem., 277, 44357–44365.
Vladusic EA, Hornby AE, Guerra-Vladusic FK, Lakins J and Lupu R . (2000). Oncol. Rep., 7, 157–167.
White MF . (1998). Mol. Cell. Biochem., 182, 3–11.
Yee D and Lee AVJ . (2000). J Mammary Gland Biol. Neopl., 5, 107–115.
Yenush L and White MF . (1997). BioEssays, 19, 491–500.
Acknowledgements
This research was supported in part by the following grants and awards: DOD Breast Cancer Research Program DAMD17-99-1-9407 (ES), DAMD17-01-1-0651 (ES), DAMD17-01-1-0320 (SdR), NIH CA87391 (ERS); Cancer Research Foundation of America F55401 (CG and ES).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Morelli, C., Garofalo, C., Sisci, D. et al. Nuclear insulin receptor substrate 1 interacts with estrogen receptor α at ERE promoters. Oncogene 23, 7517–7526 (2004). https://doi.org/10.1038/sj.onc.1208014
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208014
Keywords
This article is cited by
-
The beneficial androgenic action of steroidal aromatase inactivators in estrogen-dependent breast cancer after failure of nonsteroidal drugs
Cell Death & Disease (2019)
-
Adipocytes induce distinct gene expression profiles in mammary tumor cells and enhance inflammatory signaling in invasive breast cancer cells
Scientific Reports (2018)
-
Tsc1 deficiency impairs mammary development in mice by suppression of AKT, nuclear ERα and cell-cycle-driving proteins
Scientific Reports (2016)
-
GPER mediates the Egr-1 expression induced by 17β-estradiol and 4-hydroxitamoxifen in breast and endometrial cancer cells
Breast Cancer Research and Treatment (2012)
-
Farnesoid X receptor inhibits tamoxifen-resistant MCF-7 breast cancer cell growth through downregulation of HER2 expression
Oncogene (2011)