Chemotherapy is one of the most common strategies for
tumor treatment but often associated with post-
therapy tumor recurrence. While chemotherapeutic drugs are known to induce
tumor cell senescence, the roles and mechanisms of senescence in
tumor recurrence remain unclear. In this study, we used
doxorubicin to induce senescence in
breast cancer cells, followed by culture of
breast cancer cells with conditional media of senescent
breast cancer cells (indirect co-culture) or directly with senescent
breast cancer cells (direct co-culture). We showed that
breast cancer cells underwent the epithelial-mesenchymal transition (EMT) to a greater extent and had stronger migration and invasion ability in the direct co-culture compared with that in the indirect co-culture model. Moreover, in the direct co-culture model, non-senescent
breast cancer cells facilitated senescent
breast cancer cells to escape and re-enter into the cell cycle. Meanwhile, senescent
breast cancer cells regained
tumor cell characteristics and underwent EMT after direct co-culture. We found that the Notch signaling was activated in both senescent and non-senescent
breast cancer cells in the direct co-culture group. Notably, the EMT process of senescent and adjacent
breast cancer cells was blocked upon inhibition of Notch signaling with N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenyl]
glycine-1,1-dimethylethyl
ester (
DAPT) in the direct co-cultures. In addition,
DAPT inhibited the lung
metastasis of the co-cultured
breast cancer cells in vivo. Collectively, data arising from this study suggest that both senescent and adjacent non-senescent
breast cancer cells developed EMT through activating Notch signaling under conditions of intratumoral heterogeneity caused by
chemotherapy, which infer the possibility that Notch inhibitors used in combination with chemotherapeutic agents may become an effective treatment strategy.