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Triple-negative breast cancer (TNBC), defined as a tumor subtype that lacks ER, PR, and HER2, shows a poor prognosis due to its aggressive tumor biology and limited treatment options. Deregulation of Aurora kinase A (Aur-A), a member of the mitotic serine/threonine Aurora kinase family, and overactivation of the mTOR pathway commonly occur in multiple cancer types. We previously found that Aur-A activated the mTOR pathway and inhibited autophagy activity in breast cancer cell models. Whether and how Aur-A regulates mTOR in TNBC are still unclear. Here, we found that Aur-A and p-mTOR are highly expressed and positively associated with each other in TNBC cells and tissues. Inhibition or knockdown of Aur-A decreased p-mTOR and suppressed cell proliferation and migration, whereas overexpression of Aur-A increased p-mTOR levels and promoted cell proliferation and migration, which was significantly abrogated by simultaneous silencing of mTOR. Intriguingly, overexpression of Aur-A enhanced the expression of p-mTOR and p-ERK1/2, and silencing or inhibition of ERK1/2 blocked Aur-A-induced p-mTOR. However, silencing or inhibition of mTOR failed to reverse Aur-A-induced ERK1/2, indicating that Aur-A/ERK1/2/mTOR forms an oncogenic cascade in TNBC. We finally found that double inhibition of Aur-A and mTOR showed significant synergistic effects in TNBC cell lines and a xenograft model, indicating that Aur-A and mTOR are potential therapeutic targets in the TNBC subtype.

Aurora-A/ERK1/2/mTOR axis promotes tumor progression in triple-negative breast cancer and dual-targeting Aurora-A/mTOR shows synthetic lethality