Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression
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Guangchao Li1,*, Likun Zhao1,*, Wei Li2,4, Kexing Fan2,4, Weizhu Qian3, Sheng Hou2,3,4, Hao Wang2,3,4, Jianxin Dai2,3,4, Huafeng Wei2,3,4, and Yajun Guo1,2,3,4
1 School of Bioscience and Bioengneering, South China University of Technology, Guangzhou, China
2 International Joint Cancer Institute, Second Military Medical University, Shanghai, China
3 State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, China
4 School of Pharmacy, Liaocheng University, Liaocheng, Shandong Provence, China
* These authors contributed equally to the work
Huafeng Wei, email:
Jianxin Dai, email:
Keywords: HER2; trastuzumab resistance; STAT3; MUC1/4; feedback loop
Received: April 23, 2014 Accepted: June 24, 2014 Published: June 26, 2014
Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer.
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