versican g3 domain modulates breast cancer cell apoptosis a mechanism for breast cancer cell response to chemotherapy and egfr therapyversican g3域调节乳腺癌细胞凋亡的机制乳腺癌细胞对化疗和表皮生长因子受体疗法.pdfVIP

Versican G3 Domain Modulates Breast Cancer Cell Apoptosis: A Mechanism for Breast Cancer Cell Response to Chemotherapy and EGFR Therapy William Weidong Du1,2, Burton B. Yang2,3, Bing L. Yang1,2, Zhaoqun Deng2,3, Ling Fang2,3, Sze Wan 2,3 2,3 4 2,3 1 Shan , Zina Jeyapalan , Yaou Zhang , Arun Seth , Albert J. Yee * 1 Department of Surgery, Sunnybrook Health Sciences Centre and Centre for the Study of Bone Metastasis, Odette Cancer Centre, University of Toronto, Toronto, Canada, 2 Sunnybrook Research Institute, Toronto, Canada, 3 Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada, 4 Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China Abstract Overexpression of EGFR and versican has been reported in association with breast cancers. Considered oncogenic, these molecules may be attractive therapeutic targets. Possessing anti-apoptotic and drug resistant properties, overexpression of these molecules is accompanied by selective sensitization to the process of apoptosis. In this study, we exogenously expressed a versican G3 construct in breast cancer cell lines and analyzed the effects of G3 on cell viability in fetal bovine serum free conditioned media and evaluated the effects of apoptotic agent C2-ceramide, and chemotherapeutic agents including Docetaxel, Doxorubicin, and Epirubicin. Versican G3 domain enhanced tumor cell resistance to apoptosis when cultured in serum free medium, Doxorubicin, or Epirubicin by up-regulating pERK and GSK-3b (S9P). However, it could be prevented by selective EGFR inhibitor AG 1478 and selective MEK inhibitor PD 98059. Both AG 1478 and PD 98059 enhanced expression of pSAPK/JNK, while selective JNK inhibitor SP 600125 enhanced expression of GSK