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Objective To investigate the role of human mesenchymal stem cells (hMSCs) in regulating the chemosensitivity of breast cancer cells and to dissect the underlying molecular mechanism.Methods The human umbilical cord mesenchymal stem cells (hUC-MSCs) were previously isolated and identified in our own lab.The expression of several ligands of receptor tyrosine kinases including Neuregulin-1 (NRG-1, also Heregulin-β1), NRG-2, IGF-?, IGF-?, and EGF were assayed with regular RT-PCR.The conditioned medium of hUC-MSCs (CM_MSCs) was harvested using Millipore Amicon Ultra Centrifugal Filters (3K).Breast cancer cells with (SKBR3, MDA-MB-453, and BT474) or without (MDA-MB-231) overexpressions of erbB2 were treated with CM_MSCs.The activation of PI3K-Akt signaling pathway was detected with western blot analysis.Cell proliferation assays were carried out to evaluate the chemosensitivity of breast cancer cells treated with CM_MSCs.Apoptotic ELISA assays was used to quantitatively measure apoptosis.Lentiviral erbB3-overexpressing or shRNA-expressing systems were applied to introduce overexpression or specifically knock-down the expression of erbB3 in breast cancer cells, respectively.Results The NRG-1, NRG-2, IGF-?, IGF-?, and EGF were simultaneously expressed in hUC-MSCs with different mRNAs expression levels.The presence of NRG-1 in the conditioned medium of hUC-MSCs (CM_MSCs) was also verified with western blot analysis.Upon treatment with CM_MSCs, only erbB2-overexpressing breast cancer cells (SKBR3, MDA-MB-453, and BT474) showed significant activation of PI3K-Akt signaling pathway, an effect comparable to that of a recombinant human NRG-1.In addition, treatment with CM_MSCs not only decreased the anti-proliferation effect of paclitaxel on erbB2-overexpressing breast cancer cells, but also significantly inhibited paclitaxel-induced apoptosis.Meanwhile, SKBR3 with overexpression of erbB3 showed enhanced CM_MSCs-induced paclitaxel-resistance as compared with control.On the contrary, specifically knocking down the expression of erbB3 in MDA-MB-453 abrogated the effect of CM_MSCs on chemo-sensitivity.Conclusion We reported here that human mesenchymal stem cells selectively induced paclitaxel-resistance in erbB2-overexpressing breast cancer cells via activation of PI3K-Akt signaling pathway.Thus, mesenchymal stem cells may act as a potential therapeutic target in erbB2-overexpressing breast cancer treatment.