DYNLT1-TP53BP2 axis drives tamoxifen resistance in breast cancer by activating PI3K/Akt/mTOR signaling.

AIMS: Tamoxifen resistance constitutes a major clinical obstacle in managing ER+ breast cancer (BC). Although DYNLT1 has been linked to tumor development and progression, its function in modulating tamoxifen resistance in BC is still ambiguous. MATERIALS AND METHODS: DYNLT1 expression was evaluated in BC through immunohistochemistry, real-time PCR, and Western blotting. The functional impact of DYNLT1 on tamoxifen resistance was assessed in vitro and in vivo models. The mechanism by which DYNLT1 activates the PI3K/Akt/mTOR signaling pathway was examined through Western blotting, co-immunoprecipitation, immunofluorescence, and cycloheximide chase assays. The regulation of DYNLT1 mRNA by HUR was investigated using real-time PCR, RNA immunoprecipitation, and actinomycin-D-based RNA stability assays. KEY FINDINGS: DYNLT1 expression was markedly elevated in tamoxifen-resistant BC. Elevated DYNLT1 levels are linked to diminished recurrence-free survival in patients undergoing adjuvant tamoxifen therapy. Functionally, DYNLT1 overexpression induced tamoxifen resistance both in vitro and in vivo. Mechanistically, DYNLT1 interacted with TP53BP2, facilitating its degradation and alleviating p85α-mediated suppression of the PI3K/Akt/mTOR signaling. Suppression of this signaling axis enhanced tamoxifen sensitivity in BC cells and xenografts. HuR maintains DYNLT1 expression by stabilizing its mRNA in association with m6A modification. SIGNIFICANCE: These results reveal a new mechanism for PI3K/Akt/mTOR signaling activation in tamoxifen-resistant BC, driven by DYNLT1-mediated TP53BP2 degradation. This identifies DYNLT1 as a promising prognostic indicator and therapeutic intervention for tamoxifen resistance.