Differential insulin-like growth factor I receptor signaling and function in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells.

The insulin-like growth factor I receptor (IGF-IR) is a ubiquitous and multifunctional tyrosine kinase that has been implicated in breast cancer development. In estrogen receptor (ER)-positive breast tumors, the levels of the IGF-IR and its substrate, insulin-receptor substrate 1 (IRS-1), are often elevated, and these characteristics have been linked with increased radioresistance and cancer recurrence. In vitro, activation of the IGF-IR/IRS-1 pathway in ER-positive cells improves growth and counteracts apoptosis induced by anticancer treatments. The function of the IGF-IR in hormone-independent breast cancer is not clear. ER-negative breast cancer cells often express low levels of the IGF-IR and fail to respond to IGF-I with mitogenesis. On the other hand, anti-IGF-IR strategies effectively reduced metastatic potential of different ER-negative cell lines, suggesting a role of this receptor in late stages of the disease. Here we examined IGF-IR signaling and function in ER-negative MDA-MB-231 breast cancer cells and their IGF-IR-overexpressing derivatives. We demonstrated that IGF-I acts as a chemoattractant for these cells. The extent of IGF-I-induced migration reflected IGF-IR levels and required the activation of phosphatidylinositol 3-kinase (PI-3K) and p38 kinases. The same pathways promoted IGF-I-dependent motility in ER-positive MCF-7 cells. In contrast with the positive effects on cell migration, IGF-I was unable to stimulate growth or improve survival in MDA-MB-231 cells, whereas it induced mitogenic and antiapoptotic effects in MCF-7 cells. Moreover, IGF-I partially restored growth in ER-positive cells treated with PI-3K and ERK1/ERK2 inhibitors, whereas it had no protective effects in ER-negative cells. The impaired IGF-I growth response of ER-negative cells was not caused by a low IGF-IR expression, defective IGF-IR tyrosine phosphorylation, or improper tyrosine phosphorylation of IRS-1. Also, the acute (15-min) IGF-I activation of PI-3 and Akt kinases was similar in ER-negative and ER-positive cells. However, a chronic (2-day) IGF-I exposure induced the PI-3K/Akt pathway only in MCF-7 cells. The reactivation of this pathway in ER-negative cells by overexpression of constitutively active Akt mutants was not sufficient to significantly improve proliferation or survival (with or without IGF-I), which indicated that other pathways are also required to support these functions. Our results suggest that in breast cancer cells, IGF-IR can control nonmitogenic processes regardless of the ER status, whereas IGF-IR growth-related functions may depend on ER expression.

[1]  A. Benner,et al.  Down‐regulation of insulin‐like growth factor‐I receptor and insulin receptor substrate‐1 expression in advanced human breast cancer , 2000, International journal of cancer.

[2]  G. Nemerow,et al.  Urokinase Plasminogen Activator/Urokinase-specific Surface Receptor Expression and Matrix Invasion by Breast Cancer Cells Requires Constitutive p38α Mitogen-activated Protein Kinase Activity* , 2000, The Journal of Biological Chemistry.

[3]  B. Vanhaesebroeck,et al.  The PI3K-PDK1 connection: more than just a road to PKB. , 2000, The Biochemical journal.

[4]  Adrian V. Lee,et al.  Insulin-Like Growth Factor I-Induced Degradation of Insulin Receptor Substrate 1 Is Mediated by the 26S Proteasome and Blocked by Phosphatidylinositol 3′-Kinase Inhibition , 2000, Molecular and Cellular Biology.

[5]  D J Glass,et al.  Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. , 1999, Science.

[6]  K. Moelling,et al.  Phosphorylation and regulation of Raf by Akt (protein kinase B). , 1999, Science.

[7]  R. Baserga.  The IGF-I receptor in cancer research. , 1999, Experimental cell research.

[8]  A. Agarwal,et al.  Epidermal growth factor promotes MDA-MB-231 breast cancer cell migration through a phosphatidylinositol 3'-kinase and phospholipase C-dependent mechanism. , 1999, Cancer research.

[9]  S. Andò,et al.  SHC–α5β1 Integrin Interactions Regulate Breast Cancer Cell Adhesion and Motility , 1999 .

[10]  B. Calabretta,et al.  Multiple Signaling Pathways of the Insulin-Like Growth Factor 1 Receptor in Protection from Apoptosis , 1999, Molecular and Cellular Biology.

[11]  D. Yee,et al.  IRS-1 expression and activation are not sufficient to activate downstream pathways and enable IGF-I growth response in estrogen receptor negative breast cancer cells. , 1999, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[12]  E. Surmacz,et al.  The activated insulin-like growth factor I receptor induces depolarization in breast epithelial cells characterized by actin filament disassembly and tyrosine dephosphorylation of FAK, Cas, and paxillin. , 1999, Experimental cell research.

[13]  J. Swantek,et al.  Prolonged activation of ERK2 by epidermal growth factor and other growth factors requires a functional insulin-like growth factor 1 receptor. , 1999, Endocrinology.

[14]  S. Kassis,et al.  p38 mitogen-activated protein kinase inhibitors--mechanisms and therapeutic potentials. , 1999, Pharmacology & therapeutics.

[15]  S. Hilsenbeck,et al.  Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. , 1999, Molecular endocrinology.

[16]  Sandra,et al.  A dominant negative mutant of the insulin-like growth factor-I receptor inhibits the adhesion, invasion, and metastasis of breast cancer. , 1998, Cancer research.

[17]  K. Siddle,et al.  Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. , 1998, The Biochemical journal.

[18]  F. Hobbs,et al.  Identification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase* , 1998, The Journal of Biological Chemistry.

[19]  K. Reiss,et al.  Molecular markers of IGF-I-mediated mitogenesis. , 1998, Experimental cell research.

[20]  David J Hunter,et al.  Circulating concentrations of insulin-like growth factor I and risk of breast cancer , 1998, The Lancet.

[21]  D. Yee,et al.  Insulin Receptor Substrate-1 is the Predominant Signaling Molecule Activated by Insulin-like Growth Factor-I, Insulin, and Interleukin-4 in Estrogen Receptor-positive Human Breast Cancer Cells* , 1998, The Journal of Biological Chemistry.

[22]  N. Webster,et al.  Elevated insulin-like growth factor I receptor autophosphorylation and kinase activity in human breast cancer. , 1998, Cancer research.

[23]  B. van der Burg,et al.  Mitogenic Signaling of Insulin-like Growth Factor I in MCF-7 Human Breast Cancer Cells Requires Phosphatidylinositol 3-Kinase and Is Independent of Mitogen-activated Protein Kinase* , 1997, The Journal of Biological Chemistry.

[24]  M. Prisco,et al.  Differential roles of IRS‐1 and SHC signaling pathways in breast cancer cells , 1997, International journal of cancer.

[25]  P. Glazer,et al.  Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation. , 1997, Cancer research.

[26]  E. Surmacz,et al.  Tamoxifen interferes with the insulin-like growth factor I receptor (IGF-IR) signaling pathway in breast cancer cells. , 1997, Cancer research.

[27]  R. Hardman,et al.  Insulin-like growth factor 1 (IGF-1) alters drug sensitivity of HBL100 human breast cancer cells by inhibition of apoptosis induced by diverse anticancer drugs. , 1997, Cancer research.

[28]  E. Surmacz,et al.  Overexpressed IGF-I receptors reduce estrogen growth requirements, enhance survival, and promote E-cadherin-mediated cell-cell adhesion in human breast cancer cells. , 1997, Experimental cell research.

[29]  M. Rubini,et al.  The IGF-I receptor in mitogenesis and transformation of mouse embryo cells: role of receptor number. , 1997, Experimental cell research.

[30]  B. Gliozzo,et al.  Insulin‐like Growth Factor‐I (IGF‐I) Receptors in Breast Cancer , 1996, Annals of the New York Academy of Sciences.

[31]  M E Doerr,et al.  The Roles of Integrins and Extracellular Matrix Proteins in the Insulin-like Growth Factor I-stimulated Chemotaxis of Human Breast Cancer Cells (*) , 1996, The Journal of Biological Chemistry.

[32]  C. Roberts,et al.  Growth inhibition of MCF-7 breast cancer cells by stable expression of an insulin-like growth factor I receptor antisense ribonucleic acid. , 1995, Endocrinology.

[33]  N. Rosen,et al.  Insulin and insulin-like growth factor signaling are defective in the MDA MB-468 human breast cancer cell line. , 1994, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[34]  K Y Hui,et al.  A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). , 1994, The Journal of biological chemistry.

[35]  A. Costantino,et al.  Insulin-resistant MDA-MB231 human breast cancer cells contain a tyrosine kinase inhibiting activity. , 1993, Molecular endocrinology.

[36]  D. Kerr,et al.  The response of breast cancer cells to steroid and peptide growth factors. , 1992, Anticancer research.

[37]  C. Osborne,et al.  Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. , 1989, The Journal of clinical investigation.

[38]  P. Tsichlis,et al.  AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. , 1999, Annual review of biochemistry.

[39]  S. Hilsenbeck,et al.  Insulin-like growth factor binding protein-3 and insulin receptor substrate-1 in breast cancer: correlation with clinical parameters and disease-free survival. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[40]  M. Railo,et al.  The prognostic value of insulin-like growth factor-I in breast cancer patients. Results of a follow-up study on 126 patients. , 1994, European journal of cancer.

[41]  J. Bonneterre,et al.  Characterization of insulin-like growth factor 1 receptors (IGF1-R) in human breast cancer cell lines. , 1989, Bulletin du cancer.