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Your search keyword '"Napolitano, Maria"' showing total 6 results
Start Over Author "Napolitano, Maria" Journal breast cancer research and treatment
6 results on '"Napolitano, Maria"'

6. Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells.

Author

D'Alessio A, De Luca A, Maiello MR, Lamura L, Rachiglio AM, Napolitano M, Gallo M, and Normanno N

Subjects
Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal, Humanized, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p27, Drug Synergism, ErbB Receptors metabolism, Female, Forkhead Box Protein O3, Forkhead Transcription Factors metabolism, Gefitinib, Humans, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Lapatinib, Mitogen-Activated Protein Kinases metabolism, Phosphorylation, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt metabolism, Quinazolines pharmacology, RNA Interference, RNA, Messenger genetics, RNA, Messenger metabolism, Receptor, ErbB-2 metabolism, Retinoblastoma-Like Protein p130 metabolism, Time Factors, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols pharmacology, Breast Neoplasms enzymology, Cell Cycle drug effects, Cell Cycle Proteins metabolism, ErbB Receptors antagonists & inhibitors, Receptor, ErbB-2 antagonists & inhibitors, Signal Transduction drug effects
Abstract

Treatment of breast cancer cells with a combination of the EGFR-tyrosine kinase inhibitor (EGFR-TKI) gefitinib and the anti-ErbB-2 monoclonal antibody trastuzumab results in a synergistic antitumor effect. In this study, we addressed the mechanisms involved in this phenomenon. The activation of signaling pathways and the expression of cell cycle regulatory proteins were studied in SK-Br-3 and BT-474 breast cancer cells, following treatment with EGFR and/or ErbB-2 inhibitors. Treatment with the gefitinib/trastuzumab combination produced, as compared with a single agent, a more prolonged blockade of AKT and MAPK activation, a more pronounced accumulation of cells in the G0/G1 phase of the cell cycle, a more significant increase in the levels of p27(kip1) and of hypophosphorylated pRb2, and a decrease in the levels of Cyclin D1 and survivin. Similar findings were observed with the EGFR/ErbB-2 inhibitor lapatinib. Gefitinib, trastuzumab, and their combination increased the stability of p27(kip1), with the combination showing the highest effects. Blockade of both receptors with gefitinib/trastuzumab or lapatinib induced a significant increase in the levels of p27(kip1) mRNA and in the nuclear levels of the p27(kip1) transcription factor FKHRL-1. Inhibition of PI3K signaling also produced a significant raise in p27(kip1) mRNA. Finally, down-modulation of FKHRL-1 with siRNAs prevented the lapatinib-induced increase of p27(kip1) mRNA. The synergism deriving from EGFR and ErbB-2 blockade is mediated by several different alterations in the activation of signaling proteins and in the expression of cell cycle regulatory proteins, including transcriptional and posttranscriptional regulation of p27(kip1) expression.

Published
2010
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