Abstract
Abstract HER3 is reported to be overexpressed in 18-29% of human breast cancers and suggested to be a marker of reduced disease-specific survival in 4,406 patients with invasive breast carcinoma. Overexpression and subcellular localization of HER3 may be a negative predictive marker for targeted therapies, and HER3 status may play a role in the development of drug resistance and metastasis. Translocation of ERBB family members EGFR, HER2 and HER4 into nucleus for regulating gene transcription have been reported, but only a few studies about nuclear HER3 have been reported and the biological role of nuclear HER3 is still unknown. HER3 was detected in the nucleus of 57% in Japanese lung cancers, and has also been detected in the nuclei of prostate cancers and other cancer cell lines. A study suggested that nuclear HER3 by IHC is associated with favorable overall survival in 128 uveal melanoma patients. The potential mechanism of HER3 translocation and its role on drug resistance was intensively studied in the work. According to our observation, nuclear HER3 was found to be significantly increased in HER2-positive breast cancer cells SKBr3 during an EGFR-targeted therapy Iressa, and increased sub-band of HER3 was detected by Western blot in the Iressa-resistant SKBr3 cells. The Iressa-induced HER3 nuclear localization in SKBr3 and BT474 cells can be inhibited by the application of ADAM17 and gamma-secretase inhibitors or siRNA, the additional inhibitors can sensitize the cells to Iressa treatment which may be a new target for preventing HER3-mediated drug resistance. If the HER3 subcellular localization is important for cancer development and drug resistance, inhibitor for this pathway will enhance the efficiency of recent therapies on breast cancer. Citation Format: Patrick Ming Kuen Tang, Ui Soon Khoo, Adrian L. Harris, Anthony Kong. The role of nuclear HER3 in breast cancer resistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3334. doi:10.1158/1538-7445.AM2014-3334
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