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Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells.
Int J Cancer. 2004 Jan 20; 108(3):334-41.IJ

Abstract

The clinical usefulness of trastuzumab (Herceptin; Genentech, San Francisco, CA) in breast cancer treatment is limited by the rapid development of resistance. We previously reported that IGF-I signaling confers resistance to the growth-inhibitory actions of trastuzumab in a model system, but the underlying molecular mechanism remains unknown. We used SKBR3/neo cells (expressing few IGF-I receptors) and SKBR3/IGF-IR cells (overexpressing IGF-I receptor) as our experimental model. IGF-I antagonized the trastuzumab-induced increase in the level of the Cdk inhibitor p27(Kip1). This resulted in decreased association of p27(Kip1) with Cdk2, restoration of Cdk2 activity and attenuation of cell-cycle arrest in G(1) phase, all of which had been induced by trastuzumab treatment in SKBR3/IGF-IR cells. We also found that the decrease in p27(Kip1) induced by IGF-I was accompanied by an increase in expression of Skp2, which is a ubiquitin ligase for p27(Kip1), and by increased Skp2 association with p27(Kip1). A specific proteasome inhibitor (LLnL) completely blocked the ability of IGF-I to reduce the p27(Kip1) protein level, while IGF-I increased p27(Kip1) ubiquitination. This suggests that the action of IGF-I in conferring resistance to trastuzumab involves targeting of p27(Kip1) to the ubiquitin/proteasome degradation machinery. Finally, specific inhibitors of MAPK and PI3K suggest that the IGF-I-mediated reduction in p27(Kip1) protein level by increased degradation predominantly involves the PI3K pathway. Our results provide an example of resistance to an antineoplastic therapy that targets one tyrosine kinase receptor by increased signal transduction through an alternative pathway in a complex regulatory network.

Authors+Show Affiliations

Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14648698

Citation

Lu, Yuhong, et al. "Molecular Mechanisms Underlying IGF-I-induced Attenuation of the Growth-inhibitory Activity of Trastuzumab (Herceptin) On SKBR3 Breast Cancer Cells." International Journal of Cancer, vol. 108, no. 3, 2004, pp. 334-41.
Lu Y, Zi X, Pollak M. Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells. Int J Cancer. 2004;108(3):334-41.
Lu, Y., Zi, X., & Pollak, M. (2004). Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells. International Journal of Cancer, 108(3), 334-41.
Lu Y, Zi X, Pollak M. Molecular Mechanisms Underlying IGF-I-induced Attenuation of the Growth-inhibitory Activity of Trastuzumab (Herceptin) On SKBR3 Breast Cancer Cells. Int J Cancer. 2004 Jan 20;108(3):334-41. PubMed PMID: 14648698.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells. AU - Lu,Yuhong, AU - Zi,Xiaolin, AU - Pollak,Michael, PY - 2003/12/4/pubmed PY - 2004/1/24/medline PY - 2003/12/4/entrez SP - 334 EP - 41 JF - International journal of cancer JO - Int J Cancer VL - 108 IS - 3 N2 - The clinical usefulness of trastuzumab (Herceptin; Genentech, San Francisco, CA) in breast cancer treatment is limited by the rapid development of resistance. We previously reported that IGF-I signaling confers resistance to the growth-inhibitory actions of trastuzumab in a model system, but the underlying molecular mechanism remains unknown. We used SKBR3/neo cells (expressing few IGF-I receptors) and SKBR3/IGF-IR cells (overexpressing IGF-I receptor) as our experimental model. IGF-I antagonized the trastuzumab-induced increase in the level of the Cdk inhibitor p27(Kip1). This resulted in decreased association of p27(Kip1) with Cdk2, restoration of Cdk2 activity and attenuation of cell-cycle arrest in G(1) phase, all of which had been induced by trastuzumab treatment in SKBR3/IGF-IR cells. We also found that the decrease in p27(Kip1) induced by IGF-I was accompanied by an increase in expression of Skp2, which is a ubiquitin ligase for p27(Kip1), and by increased Skp2 association with p27(Kip1). A specific proteasome inhibitor (LLnL) completely blocked the ability of IGF-I to reduce the p27(Kip1) protein level, while IGF-I increased p27(Kip1) ubiquitination. This suggests that the action of IGF-I in conferring resistance to trastuzumab involves targeting of p27(Kip1) to the ubiquitin/proteasome degradation machinery. Finally, specific inhibitors of MAPK and PI3K suggest that the IGF-I-mediated reduction in p27(Kip1) protein level by increased degradation predominantly involves the PI3K pathway. Our results provide an example of resistance to an antineoplastic therapy that targets one tyrosine kinase receptor by increased signal transduction through an alternative pathway in a complex regulatory network. SN - 0020-7136 UR - https://www.unboundmedicine.com/medline/citation/14648698/Molecular_mechanisms_underlying_IGF_I_induced_attenuation_of_the_growth_inhibitory_activity_of_trastuzumab__Herceptin__on_SKBR3_breast_cancer_cells_ L2 - https://doi.org/10.1002/ijc.11445 DB - PRIME DP - Unbound Medicine ER -