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  • Mesenchymal stem cells drive paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells via paracrine of neuregulin 1.

Mesenchymal stem cells drive paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells via paracrine of neuregulin 1.

Biochemical and biophysical research communications (2018-05-02)
Jin Chen, Qun Ren, Yuanming Cai, Tingting Lin, Weimin Zuo, Jin Wang, Rong Lin, Ling Zhu, Ping Wang, Huiyue Dong, Hu Zhao, Lianghu Huang, Yunfeng Fu, Shunliang Yang, Jianming Tan, Xiaopeng Lan, Shuiliang Wang
ABSTRACT

We had previously demonstrated that increased expression of ErbB3 is required for ErbB2-mediated paclitaxel resistance in breast cancer cells. In the present study, we have explored the possible role of mesenchymal stem cells (MSCs) in regulating the paclitaxel-sensitivity of ErbB2/ErbB3-coexpressing breast cancer cells. We show that human umbilical cord-derived MSCs express significantly higher level of neuregulin-1 as compared with ErbB2/ErbB3-coexpressing breast cancer cells themselves. Coculture or treatment with conditioned medium of MSCs not only decreases the anti-proliferation effect of paclitaxel on ErbB2/ErbB3-coexpressing breast cancer cells, but also significantly inhibits paclitaxel-induced apoptosis. We further demonstrate that this MSCs-drived paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells could be attributed to upregulation of Survivin via paracrine effect of NRG-1/ErbB3/PI-3K/Akt signaling, as either specific knockdown expression of ErbB3, or blocking of downstream PI-3K/Akt signaling, or specific inhibition of Survivin can completely reverse this effect. Moreover, targeted knockdown of NRG-1 expression in MSCs abrogates theirs effect on paclitaxel sensitivity of ErbB2/ErbB3-coexpressing breast cancer cells. Taken together, our study indicate that paracrine of NRG-1 by MSCs induces paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells through PI-3K/Akt signaling-dependent upregulation of Survivin. Our findings suggest that simultaneously targeting mesenchymal stem cells in tumor microenvironment may be a novel strategy to overcome paclitaxel resistance in patients with ErbB2/ErbB3-coexpressing breast cancer.

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MISSION® esiRNA, targeting human UGT1A3