This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, L. Articles by Xia, F. Search for Related Content PubMed PubMed Citation Articles by Li, L. Articles by Xia, F.

Erlotinib Attenuates Homologous Recombinational Repair of Chromosomal Breaks in Human Breast Cancer Cells

Departments of ¹ Radiation Oncology, ² Medicine, and ³ Cancer Biology and ⁴ Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee

Requests for reprints: Fen Xia, Department of Radiation Oncology, Vanderbilt University Medical Center, The Vanderbilt Clinic, 1301 22nd Avenue South, B-902 TVC, Nashville, TN 37232-5671. Phone: 615-322-2555; Fax: 615-343-6589; E-mail: fen.xia{at}vanderbilt.edu.

Key Words: Tarceva • erlotinib • epidermal growth factor receptor (EGFR) • breast cancer • BRCA1 • H2AX • DNA damage • homologous recombination • radiation

The epidermal growth factor receptor (EGFR) family has been implicated in several cancers, including breast, and its members have become the target of novel cancer therapies. In this report, we show a novel link between erlotinib, a potent EGFR inhibitor, DNA damage, and homology-directed recombinational repair (HDR) in human breast cancer cells. Erlotinib suppresses HDR. This is not secondary to erlotinib-mediated changes in cell cycle and is associated with increased -H2AX foci, which is an in situ marker of chromosomal double-strand breaks. Both Rad51 and BRCA1 are essential components of the HDR machinery. Consistent with decreased HDR in erlotinib-treated cells, erlotinib also attenuates DNA damage-induced Rad51 foci and results in cytoplasmic retention of BRCA1. As BRCA1 is a shuttling protein and its nuclear function of promoting HDR is controlled by its subcellular localization, we further show that targeted translocation of BRCA1 to the cytoplasm enhances erlotinib sensitivity. These findings suggest a novel mechanism of action of erlotinib through its effects on the BRCA1/HDR pathway. Furthermore, BRCA1/HDR status may be an innovative avenue to enhance the sensitivity of cancer cells to erlotinib. [Cancer Res 2008;68(22):9141–6]

This article has been cited by other articles:

				M. Kriege, C. Seynaeve, H. Meijers-Heijboer, J. M. Collee, M. B.E. Menke-Pluymers, C. C.M. Bartels, M. M.A. Tilanus-Linthorst, J. Blom, E. Huijskens, A. Jager, et al. Sensitivity to First-Line Chemotherapy for Metastatic Breast Cancer in BRCA1 and BRCA2 Mutation Carriers J. Clin. Oncol., August 10, 2009; 27(23): 3764 - 3771. [Abstract] [Full Text] [PDF]