| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Endocrinology |
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [M. B., C. M., L. M., E. S.], and Department of Cellular Biology, University of Calabria, Calabria 87036, Italy [M. B., C. M., L. M., S. A.]
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.
This article has been cited by other articles:
|
|
 |
|
  G. E de Blaquiere, F. E B May, and B. R Westley Increased expression of both insulin receptor substrates 1 and 2 confers increased sensitivity to IGF-1 stimulated cell migration Endocr. Relat. Cancer, June 1, 2009; 16(2): 635 - 647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Kleinberg, T. L. Wood, P. A. Furth, and A. V. Lee Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions Endocr. Rev., February 1, 2009; 30(1): 51 - 74. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. K. Saxena, L. Taliaferro-Smith, B. B. Knight, D. Merlin, F. A. Anania, R. M. O'Regan, and D. Sharma Bidirectional Crosstalk between Leptin and Insulin-like Growth Factor-I Signaling Promotes Invasion and Migration of Breast Cancer Cells via Transactivation of Epidermal Growth Factor Receptor Cancer Res., December 1, 2008; 68(23): 9712 - 9722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. H. Ibrahim, S. A. Byron, X. Cui, A. V. Lee, and D. Yee Progesterone Receptor-B Regulation of Insulin-Like Growth Factor-Stimulated Cell Migration in Breast Cancer Cells via Insulin Receptor Substrate-2 Mol. Cancer Res., September 1, 2008; 6(9): 1491 - 1498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Bartella, S. Cascio, E. Fiorio, A. Auriemma, A. Russo, and E. Surmacz Insulin-Dependent Leptin Expression in Breast Cancer Cells Cancer Res., June 15, 2008; 68(12): 4919 - 4927. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. G. Hollier, J. A. Kricker, D. R. Van Lonkhuyzen, D. I. Leavesley, and Z. Upton Substrate-Bound Insulin-Like Growth Factor (IGF)-I-IGF Binding Protein-Vitronectin-Stimulated Breast Cell Migration Is Enhanced by Coactivation of the Phosphatidylinositide 3-Kinase/AKT Pathway by {alpha}v-Integrins and the IGF-I Receptor Endocrinology, March 1, 2008; 149(3): 1075 - 1090. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Gong, P. Guo, Y. Zhai, J. Zhou, H. Uppal, M. J. Jarzynka, W.-C. Song, S.-Y. Cheng, and W. Xie Estrogen Deprivation and Inhibition of Breast Cancer Growth in Vivo through Activation of the Orphan Nuclear Receptor Liver X Receptor Mol. Endocrinol., August 1, 2007; 21(8): 1781 - 1790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. X.-D. Song, Z. Zhang, Y. Chen, Y. Bao, and R. J. Santen Estrogen Signaling via a Linear Pathway Involving Insulin-Like Growth Factor I Receptor, Matrix Metalloproteinases, and Epidermal Growth Factor Receptor to Activate Mitogen-Activated Protein Kinase in MCF-7 Breast Cancer Cells Endocrinology, August 1, 2007; 148(8): 4091 - 4101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Sisci, C. Morelli, C. Garofalo, F. Romeo, L. Morabito, F. Casaburi, E. Middea, S. Cascio, E. Brunelli, S. Ando, et al. Expression of nuclear insulin receptor substrate 1 in breast cancer J. Clin. Pathol., June 1, 2007; 60(6): 633 - 641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Dhar, S. Banerjee, G. Dhar, K. Sengupta, and S. K. Banerjee Insulin-like Growth Factor-1 (IGF-1) Induces WISP-2/CCN5 via Multiple Molecular Cross-talks and Is Essential for Mitogenic Switch by IGF-1 Axis in Estrogen Receptor-Positive Breast Tumor Cells Cancer Res., February 15, 2007; 67(4): 1520 - 1526. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Ma, S. L. Gibson, M. A. Byrne, J. Zhang, M. F. White, and L. M. Shaw Suppression of Insulin Receptor Substrate 1 (IRS-1) Promotes Mammary Tumor Metastasis Mol. Cell. Biol., December 15, 2006; 26(24): 9338 - 9351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Maor, D. Mayer, R. I Yarden, A. V Lee, R. Sarfstein, H. Werner, and M. Z Papa Estrogen receptor regulates insulin-like growth factor-I receptor gene expression in breast tumor cells: involvement of transcription factor Sp1 J. Endocrinol., December 1, 2006; 191(3): 605 - 612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Srirangam, R. Mitra, M. Wang, J. C. Gorski, S. Badve, L. Baldridge, J. Hamilton, H. Kishimoto, J. Hawes, L. Li, et al. Effects of HIV Protease Inhibitor Ritonavir on Akt-Regulated Cell Proliferation in Breast Cancer Clin. Cancer Res., March 15, 2006; 12(6): 1883 - 1896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lin, P. M. Ridker, N. Rifai, I-M. Lee, J. E. Manson, J. E. Buring, and S. M. Zhang A Prospective Study of Hemoglobin A1c Concentrations and Risk of Breast Cancer in Women. Cancer Res., March 1, 2006; 66(5): 2869 - 2875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Garofalo, M. Koda, S. Cascio, M. Sulkowska, L. Kanczuga-Koda, J. Golaszewska, A. Russo, S. Sulkowski, and E. Surmacz Increased Expression of Leptin and the Leptin Receptor as a Marker of Breast Cancer Progression: Possible Role of Obesity-Related Stimuli Clin. Cancer Res., March 1, 2006; 12(5): 1447 - 1453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. S. Miller and D. Yee Type I Insulin-like Growth Factor Receptor as a Therapeutic Target in Cancer Cancer Res., November 15, 2005; 65(22): 10123 - 10127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Remacle-Bonnet, F. Garrouste, G. Baillat, F. Andre, J. Marvaldi, and G. Pommier Membrane Rafts Segregate Pro- from Anti-Apoptotic Insulin-Like Growth Factor-I Receptor Signaling in Colon Carcinoma Cells Stimulated by Members of the Tumor Necrosis Factor Superfamily Am. J. Pathol., September 1, 2005; 167(3): 761 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Levin Integration of the Extranuclear and Nuclear Actions of Estrogen Mol. Endocrinol., August 1, 2005; 19(8): 1951 - 1959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J M Gee, J F Robertson, E Gutteridge, I O Ellis, S E Pinder, M Rubini, and R I Nicholson Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S99 - S111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ling, L. A. Maile, J. Lieskovska, J. Badley-Clarke, and D. R. Clemmons Role of SHPS-1 in the Regulation of Insulin-like Growth Factor I-stimulated Shc and Mitogen-activated Protein Kinase Activation in Vascular Smooth Muscle Cells Mol. Biol. Cell, July 1, 2005; 16(7): 3353 - 3364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M Koda, M Sulkowska, L Kanczuga-Koda, and S Sulkowski Expression of insulin receptor substrate 1 in primary breast cancer and lymph node metastases J. Clin. Pathol., June 1, 2005; 58(6): 645 - 649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C.J.P. Gielen, E. E. Hanekamp, L. J. Blok, F. J. Huikeshoven, and C. W. Burger Steroid-Modulated Proliferation of Human Endometrial Carcinoma Cell Lines: Any Role for Insulin-like Growth Factor Signaling? Reproductive Sciences, January 1, 2005; 12(1): 58 - 64. [Abstract] [PDF]
|
|
|
|
 |
|
 X. Tian, M. R. Aruva, W. Qin, W. Zhu, K. T. Duffy, E. R. Sauter, M. L. Thakur, and E. Wickstrom External Imaging of CCND1 Cancer Gene Activity in Experimental Human Breast Cancer Xenografts with 99mTc-Peptide-Peptide Nucleic Acid-Peptide Chimeras J. Nucl. Med., December 1, 2004; 45(12): 2070 - 2082. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Oh, H.-J. List, R. Reiter, A. Mani, Y. Zhang, E. Gehan, A. Wellstein, and A. T. Riegel The Nuclear Receptor Coactivator AIB1 Mediates Insulin-like Growth Factor I-induced Phenotypic Changes in Human Breast Cancer Cells Cancer Res., November 15, 2004; 64(22): 8299 - 8308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Garofalo, D. Sisci, and E. Surmacz Leptin Interferes with the Effects of the Antiestrogen ICI 182,780 in MCF-7 Breast Cancer Cells Clin. Cancer Res., October 1, 2004; 10(19): 6466 - 6475. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Vella, R. Mineo, F. Frasca, E. Mazzon, G. Pandini, R. Vigneri, and A. Belfiore Interleukin-4 Stimulates Papillary Thyroid Cancer Cell Survival: Implications in Patients with Thyroid Cancer and Concomitant Graves' Disease J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2880 - 2889. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. X. Song, C. J. Barnes, Z. Zhang, Y. Bao, R. Kumar, and R. J. Santen The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor {alpha} to the plasma membrane PNAS, February 17, 2004; 101(7): 2076 - 2081. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Sachdev, J. S. Hartell, A. V. Lee, X. Zhang, and D. Yee A Dominant Negative Type I Insulin-like Growth Factor Receptor Inhibits Metastasis of Human Cancer Cells J. Biol. Chem., February 6, 2004; 279(6): 5017 - 5024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Moelling, K. Schad, M. Bosse, S. Zimmermann, and M. Schweneker Regulation of Raf-Akt Cross-talk J. Biol. Chem., August 16, 2002; 277(34): 31099 - 31106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhang and D. Yee Insulin-like Growth Factor Binding Protein-1 (IGFBP-1) Inhibits Breast Cancer Cell Motility Cancer Res., August 1, 2002; 62(15): 4369 - 4375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Albanell and J. Baselga Unraveling Resistance to Trastuzumab (Herceptin): Insulin-Like Growth Factor-I Receptor, a New Suspect J Natl Cancer Inst, December 19, 2001; 93(24): 1830 - 1832. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
