Trastuzumab-resistant HER2-driven breast cancer cells are sensitive to epigallocatechin-3 gallate

• Published in: Cancer research (Chicago, Ill.) Vol. 67; no. 19; pp. 9018 - 9023
• Main Authors: EDDY, Sean F, KANE, Susan E, SONENSHEIN, Gail E
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.10.2007
• Subjects: Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Catechin - analogs & derivatives; Catechin - pharmacology; Cell Growth Processes - drug effects; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Forkhead Box Protein O3; Forkhead Transcription Factors - biosynthesis; Gynecology. Andrology. Obstetrics; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Mammary gland diseases; Medical sciences; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Receptor, ErbB-2 - metabolism; Signal Transduction - drug effects; Trastuzumab; Tumors; Antineoplastic agent; erbB2 Gene; Breast cancer; Monoclonal antibody; Malignant tumor; Human Epidermal growth factor Receptor 2; Resistance; Mammary gland diseases; Epigallocatechin gallate; C-Onc gene; Anticytokine; Tumor cell; Protooncogene; Trastuzumab
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-07-1691

Overexpression of the epidermal growth factor receptor family member HER2 is found in approximately 30% of breast cancers and is a target for immunotherapy. Trastuzumab, a humanized monoclonal antibody against HER2, is cytostatic when added alone and highly successful in clinical settings when used in combination with other chemotherapeutic agents. Unfortunately, HER2 tumors in patients develop resistance to trastuzumab or metastasize to the brain, which is inaccessible to antibody therapy. Previously, we showed that the green tea polyphenol epigallocatechin-3 gallate (EGCG) inhibits growth and transformed phenotype of Her-2/neu-driven mouse mammary tumor cells. The different modes of action of EGCG and trastuzumab led us to hypothesize that EGCG will inhibit HER2-driven breast cancer cells resistant to trastuzumab. We studied trastuzumab-resistant BT474 human breast cancer cells, isolated by chronic trastuzumab exposure, and JIMT-1 breast cancer cells, derived from a pleural effusion in a patient who displayed clinical resistance to trastuzumab therapy. EGCG treatment caused a dose-dependent decrease in growth and cellular ATP production, and apoptosis at high concentrations. Akt activity was suppressed by EGCG leading to the induction of FOXO3a and target cyclin-dependent kinase inhibitor p27Kip1 levels. Thus, EGCG in combination with trastuzumab may provide a novel strategy for treatment of HER2-overexpressing breast cancers, given that EGCG can cross the blood-brain barrier.