Abstract 4091: Mesenchymal stem cells drive paclitaxel-resistance in erbB2-overexpressing breast cancer cells via paracrine of NRG-1

Breast cancer remains the most frequently diagnosed cancer and the leading cause of cancer death in women, both worldwide and in less developed countries. Surgery in conjunction with adjuvant chemotherapy is the main treatment of choice for patients with locally advanced breast cancer, leading to reduce cancer-related symptoms and prolong survival. Paclitaxel as a critical drug in the treatment of breast cancer patients, intrinsic and acquired resistance to paclitaxel represents a significant clinical problem. We had previously demonstrated that increased expression of erbB3 is required for erbB2-mediated paclitaxel resistance in breast cancer cells via PI-3K/Akt/mTOR signaling pathway-dependent upregulation of Survivin. Mesenchymal stem cells (MSCs) are emerging as an important component of tumor microenvironment, which may play an essential role in regulating cancer cell growth, motility, invasion and therapeutic resistance. In the present study, we have explored the possible role of MSCs in regulating the chemo-sensitivity of erbB2-overexpressing breast cancer cells. We show that both human umbilical cord and bone marrow-derived MSCs express significantly higher level of Neuregulin-1 (NRG-1, also Heregulin-β1) as compared with erbB2-overexpressing breast cancer cells themselves. Coculture or treatment with conditioned medium of MSCs not only decreases the anti-proliferation effect of paclitaxel on erbB2-overexpressing breast cancer cells, but also significantly inhibits paclitaxel-induced apoptosis. We further demonstrate that this MSCs-drived paclitaxel-resistance in erbB2-overexpressing breast cancer cells could be attributed to paracrine effect of NRG-1/erbB3 signaling, as specific nutralizaion of NRG-1 or blocking of erbB3 resensitizes erbB2-overexpressing breast cancer cells to paclitaxel treatment. Moreover, overexpression of erbB3 enhances, while knockdown expression of erbB3 abrogates MSCs-drived paclitaxel-resistance. Taken together, our current data indicate that paracrine of NRG-1 by MSCs induce resistance of paclitaxel in erbB2-overexpressing breast cancer cells through activation of erbB3 signaling. Our findings suggest that simultaneously targeting mesenchymal stem cells in tumor microenviroment may be a novel strategy to overcome chemotherapeutic resistance. Citation Format: Ling Zhu, Jin Wang, Weimin Zuo, Rong Lin, Tingting Lin, Yan Lei, Bingshuang Ren, Jun Lu, Huiyue Dong, Lingjing Lin, Lianghu Huang, Qinghua Wang, Yujie Ma, Hui Lyu, Bo