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Microarray-assisted pathway analysis identifies mitogen-activated protein kinase signaling as a mediator of resistance to the green tea polyphenol epigallocatechin 3-gallate in her-2/neu-overexpressing breast cancer cells.
Cancer Res. 2006 May 15; 66(10):5322-9.CR

Abstract

Overexpression of the epidermal growth factor receptor family member Her-2/neu in breast cancer leads to autophosphorylation of the receptor and induction of multiple downstream signaling pathways, including the Akt kinase to nuclear factor-kappaB (NF-kappaB) cascade that is associated with poor prognosis. Previously, we showed that the green tea polyphenol epigallocatechin 3-gallate (EGCG) inhibits growth of NF639 Her-2/neu-driven breast cancer cells via reducing receptor autophosphorylation and downstream Akt and NF-kappaB activities. Interestingly, upon prolonged culture in the presence of EGCG, cells resistant to the polyphenol could be isolated. Here, we report that resistant cells have lost tyrosine phosphorylation on the Her-2/neu receptor. Surprisingly, they displayed elevated NF-kappaB activity, and inhibition of this activity sensitized cells to EGCG. Data from microarray studies of the original and resistant NF639 populations of cells were subjected to Gene Set Enrichment Analysis pathway assessment, which revealed that the mitogen activated protein kinase (MAPK) pathway was activated in the resistant cells. Treatment of the resistant cells with the MAPK inhibitor U0216 reduced growth in soft agar and invasive phenotype, whereas the combination of EGCG and U0216 resulted in cells with a cobblestone epithelial phenotype. Thus, activation of the MAPK pathway mediates resistance to EGCG.

Authors+Show Affiliations

Department of Biochemistry and Women's Health Interdisciplinary Research Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16707458

Citation

Guo, Shangqin, et al. "Microarray-assisted Pathway Analysis Identifies Mitogen-activated Protein Kinase Signaling as a Mediator of Resistance to the Green Tea Polyphenol Epigallocatechin 3-gallate in Her-2/neu-overexpressing Breast Cancer Cells." Cancer Research, vol. 66, no. 10, 2006, pp. 5322-9.
Guo S, Lu J, Subramanian A, et al. Microarray-assisted pathway analysis identifies mitogen-activated protein kinase signaling as a mediator of resistance to the green tea polyphenol epigallocatechin 3-gallate in her-2/neu-overexpressing breast cancer cells. Cancer Res. 2006;66(10):5322-9.
Guo, S., Lu, J., Subramanian, A., & Sonenshein, G. E. (2006). Microarray-assisted pathway analysis identifies mitogen-activated protein kinase signaling as a mediator of resistance to the green tea polyphenol epigallocatechin 3-gallate in her-2/neu-overexpressing breast cancer cells. Cancer Research, 66(10), 5322-9.
Guo S, et al. Microarray-assisted Pathway Analysis Identifies Mitogen-activated Protein Kinase Signaling as a Mediator of Resistance to the Green Tea Polyphenol Epigallocatechin 3-gallate in Her-2/neu-overexpressing Breast Cancer Cells. Cancer Res. 2006 May 15;66(10):5322-9. PubMed PMID: 16707458.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Microarray-assisted pathway analysis identifies mitogen-activated protein kinase signaling as a mediator of resistance to the green tea polyphenol epigallocatechin 3-gallate in her-2/neu-overexpressing breast cancer cells. AU - Guo,Shangqin, AU - Lu,Jun, AU - Subramanian,Aravind, AU - Sonenshein,Gail E, PY - 2006/5/19/pubmed PY - 2006/7/19/medline PY - 2006/5/19/entrez SP - 5322 EP - 9 JF - Cancer research JO - Cancer Res VL - 66 IS - 10 N2 - Overexpression of the epidermal growth factor receptor family member Her-2/neu in breast cancer leads to autophosphorylation of the receptor and induction of multiple downstream signaling pathways, including the Akt kinase to nuclear factor-kappaB (NF-kappaB) cascade that is associated with poor prognosis. Previously, we showed that the green tea polyphenol epigallocatechin 3-gallate (EGCG) inhibits growth of NF639 Her-2/neu-driven breast cancer cells via reducing receptor autophosphorylation and downstream Akt and NF-kappaB activities. Interestingly, upon prolonged culture in the presence of EGCG, cells resistant to the polyphenol could be isolated. Here, we report that resistant cells have lost tyrosine phosphorylation on the Her-2/neu receptor. Surprisingly, they displayed elevated NF-kappaB activity, and inhibition of this activity sensitized cells to EGCG. Data from microarray studies of the original and resistant NF639 populations of cells were subjected to Gene Set Enrichment Analysis pathway assessment, which revealed that the mitogen activated protein kinase (MAPK) pathway was activated in the resistant cells. Treatment of the resistant cells with the MAPK inhibitor U0216 reduced growth in soft agar and invasive phenotype, whereas the combination of EGCG and U0216 resulted in cells with a cobblestone epithelial phenotype. Thus, activation of the MAPK pathway mediates resistance to EGCG. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/16707458/Microarray_assisted_pathway_analysis_identifies_mitogen_activated_protein_kinase_signaling_as_a_mediator_of_resistance_to_the_green_tea_polyphenol_epigallocatechin_3_gallate_in_her_2/neu_overexpressing_breast_cancer_cells_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16707458 DB - PRIME DP - Unbound Medicine ER -