title: Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes.
abstract: BACKGROUND
  Insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) is phosphorylated in all breast cancer subtypes. Past findings have shown that IGF-1R mediates antiestrogen resistance through cross-talk with estrogen receptor (ER) signaling and via its action upstream of the epidermal growth factor receptor and human epidermal growth factor receptor 2. Yet, the direct role of IGF-1R signaling itself in antiestrogen resistance remains obscure. In the present study, we sought to elucidate whether antiestrogen resistance is induced directly by IGF-1R signaling in response to its ligand IGF-1 stimulation.
  
  
  METHODS
  A breast cancer cell line ectopically expressing human wild-type IGF-1R, MCF7/IGF-1R, was established by retroviral transduction and colony selection. Cellular antiestrogen sensitivity was evaluated under estrogen-depleted two-dimensional (2D) and 3D culture conditions. Functional activities of the key IGF-1R signaling components in antiestrogen resistance were assessed by specific kinase inhibitor compounds and small interfering RNA.
  
  
  RESULTS
  Ectopic expression of IGF-1R in ER-positive MCF7 human breast cancer cells enhanced IGF-1R tyrosine kinase signaling in response to IGF-1 ligand stimulation. The elevated IGF-1R signaling rendered MCF7/IGF-1R cells highly resistant to the antiestrogens tamoxifen and fulvestrant. This antiestrogen-resistant phenotype involved mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase/protein kinase B pathways downstream of the IGF-1R signaling hub and was independent of ER signaling. Intriguingly, a MAPK/ERK-dependent agonistic behavior of tamoxifen at low doses was triggered in the presence of IGF-1, showing a mild promitogenic effect and increasing ER transcriptional activity.
  
  
  CONCLUSIONS
  Our data provide evidence that the IGF-1/IGF-1R signaling axis may play a causal role in antiestrogen resistance of breast cancer cells, despite continuous suppression of ER transcriptional function by antiestrogens.
authors: Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
authors: Yinghui
authors: Y
authors: Zhang
authors: Marja
authors: M
authors: Moerkens
authors: Sreenivasa
authors: S
authors: Ramaiahgari
authors: Hans
authors: H
authors: de Bont
authors: Leo
authors: L
authors: Price
authors: John
authors: J
authors: Meerman
authors: Bob
authors: B
authors: van de Water
references: J Biol Chem. 2004 Feb 6;279(6):5017-24
references: 14615489
references: Exp Cell Res. 1997 Feb 25;231(1):149-62
references: 9056422
references: J Mammary Gland Biol Neoplasia. 2008 Dec;13(4):423-9
references: 19003523
references: Br J Cancer. 1999 Feb;79(5-6):693-700
references: 10070856
references: Breast Cancer Res Treat. 2009 Mar;114(2):263-75
references: 18409071
references: Hum Pathol. 2003 Aug;34(8):803-8
references: 14506643
references: Bioinformatics. 2003 Dec 12;19(18):2448-55
references: 14668230
references: Expert Opin Biol Ther. 2008 Feb;8(2):221-34
references: 18194078
references: Biochim Biophys Acta. 2009 Jan;1795(1):62-81
references: 18804516
references: Steroids. 2009 Jul;74(7):586-94
references: 19138696
references: Int J Cancer. 2010 Jan 15;126(2):545-62
references: 19609946
references: J Steroid Biochem Mol Biol. 2010 Feb 28;118(4-5):219-30
references: 19815064
references: Biochem Biophys Res Commun. 2000 Dec 29;279(3):955-60
references: 11162456
references: Clin Cancer Res. 1995 Nov;1(11):1429-36
references: 9815941
references: Mol Endocrinol. 2003 May;17(5):792-803
references: 12586845
references: Endocr Rev. 2008 Apr;29(2):217-33
references: 18216219
references: N Engl J Med. 1998 Nov 26;339(22):1609-18
references: 9828250
references: Nat Rev Cancer. 2009 Sep;9(9):631-43
references: 19701242
references: Growth Horm IGF Res. 2002 Aug;12(4):193-7
references: 12175651
references: Cancer Lett. 2007 Oct 18;256(1):1-24
references: 17475399
references: Cancer Res. 2008 Dec 15;68(24):10238-46
references: 19074892
references: Cancer Res. 2008 Feb 1;68(3):826-33
references: 18245484
references: Biostatistics. 2003 Apr;4(2):249-64
references: 12925520
references: Oncology. 2009;77 Suppl 1:23-37
references: 20130429
references: Radiother Oncol. 2010 Aug;96(2):204-8
references: 20338651
references: Cancer Res. 2006 Dec 15;66(24):11954-66
references: 17178894
references: J Mammary Gland Biol Neoplasia. 2000 Jan;5(1):95-105
references: 10791772
references: Curr Protoc Immunol. 2001 May;Chapter 10:Unit 10.17C
references: 18432682
references: Nat Rev Cancer. 2007 Sep;7(9):713-22
references: 17721435
references: Clin Cancer Res. 2009 Jan 1;15(1):226-37
references: 19118050
references: Curr Pharm Des. 2007;13(7):705-17
references: 17346185
references: Clin Cancer Res. 2008 Oct 15;14(20):6364-70
references: 18927274
references: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2359-64
references: 19174523
references: Biochemistry (Mosc). 2003 Jun;68(6):703-4; author reply 705-6
references: 12947966
references: Cancer Res. 1995 Aug 1;55(15):3331-8
references: 7614468
references: Cancer Res. 2008 Oct 1;68(19):8022-30
references: 18829560
references: Nature. 2008 Dec 4;456(7222):663-6
references: 19005469
references: Ann Oncol. 2007 Aug;18(8):1289-91
references: 17693644
references: Cancer Res. 2002 Jul 15;62(14):3985-91
references: 12124331
references: J Cell Biochem. 1999 Feb 1;72(2):294-310
references: 10022512
references: J Natl Cancer Inst. 1990 Jul 4;82(13):1107-12
references: 2359136
references: Oncogene. 2010 Jan 14;29(2):251-62
references: 19838209
references: Bioorg Med Chem Lett. 1998 Oct 20;8(20):2839-44
references: 9873633
references: Cancer Res. 2010 Feb 1;70(3):1204-14
references: 20103628
references: J Steroid Biochem Mol Biol. 2007 Aug-Sep;106(1-5):102-10
references: 17616457
references: Cell Cycle. 2004 Mar;3(3):372-9
references: 14726697
references: Mol Cancer Res. 2003 Feb;1(4):300-11
references: 12612058
references: Nat Protoc. 2006;1(3):1112-6
references: 17406391
references: J Natl Cancer Inst. 2004 Jun 16;96(12):926-35
references: 15199112
references: Cancer Cell. 2004 Jun;5(6):597-605
references: 15193262
references: Breast Cancer Res Treat. 2010 Aug;123(1):87-96
references: 19911269
references: Eur J Cancer Clin Oncol. 1983 May;19(5):615-21
references: 6683633
references: Endocrinology. 2005 Nov;146(11):4609-18
references: 16037379
references: Cancer Res. 2001 Sep 15;61(18):6747-54
references: 11559546
references: Arch Physiol Biochem. 2009 May;115(2):58-71
references: 19485702
references: Front Biosci. 2008 May 01;13:3906-12
references: 18508484