Abstract C186: Tyro3 is a potential target for the treatment of breast cancer

• Published in: Molecular cancer therapeutics 2013-11, Vol.12 (11_Supplement), p.C186-C186
• Main Authors: Ekyalongo, Roudy Chiminch, Mukohara, Toru, Funakoshi, Yohei, Tomioka, Hideo, Kataoka, Yu, Shimono, Yohei, Toyoda, Masanori, Kiyota, Naomi, Fujiwara, Yutaka, Minami, Hironobu
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-13-C186

Background: We previously identified the involvement of receptor tyrosine kinase Tyro3 in the cell growth mechanism of MCF-7 breast cancer cells. In the present study, we evaluated the potential of Tyro3 as a therapeutic target in various types of breast cancer cell lines. Material and Methods: We compared outcomes following Tyro3 knockdown by siRNA in four estrogen receptor (ER)-positive/HER2-nonamplified (luminal-type; CAMA-1, T47D, MCF-7, and HCC1428), two ER-negative/HER2-amplified (HER2-type; HCC1419 and HCC1954), and two ER-negative/HER2-nonamplified (triple negative [TN]-type; MDA-MB-231 and HCC1143) breast cancer cell lines. The effect of Tyro3 knockdown on cell growth, cell cycle distribution, and cell signaling was evaluated by MTS assay, FACS, and Western blot, respectively. Results: Tyro3 knockdown by siRNA induced the most prominent growth suppression in luminal-type cells, and to a lesser extent in HER2-type cells. In contrast, no growth inhibition following Tyro3 knockdown was observed in TN-type cells. The Tyro3 siRNA-induced growth inhibition in luminal-type cells was observed in both the estradiol (E2)-rich and -null conditions. Cellular sensitivity to Tyro3 siRNA was not correlated with baseline Tyro3 expression level or level of secretion of Tyro3 ligand Gas6. Phosphorylation of Tyro3 was detectable in five of six sensitive lines, but not in two resistant TN-type lines. The results of the growth assays significantly correlated with those of FACS analysis, with G0-G1/S cell cycle arrest observed only in Tyro3 siRNA-sensitive cells. Western blot analysis showed a decrease in phosphorylation of downstream signaling molecules, including ERK1/2, S6K, and STAT3, and in cyclin D1 in cell lines sensitive to Tyro3 siRNA only, and not in resistant TN-type cell lines. Conclusions: Tyro3 is a potential therapeutic target in breast cancer, particularly in luminal-type cells. Phosphorylation of Tyro3 might be a predictive marker of sensitivity to Tyro3-targeted therapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C186. Citation Format: Roudy Chiminch Ekyalongo, Toru Mukohara, Yohei Funakoshi, Hideo Tomioka, Yu Kataoka, Yohei Shimono, Masanori Toyoda, Naomi Kiyota, Yutaka Fujiwara, Hironobu Minami. Tyro3 is a potential target for the treatment of breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cance