TRPS1 confers paclitaxel resistance in TNBC through dual activation of the PDE4D–cAMP–AKT pathway and microtubule destabilization

Triple-negative breast cancer (TNBC) is an aggressive subtype that lacks effective targeted therapies and frequently develops resistance to paclitaxel, with the underlying mechanisms remaining incompletely understood. Clinically, elevated TRPS1 expression was significantly associated with poor pathological response to neoadjuvant chemotherapy and reduced overall survival in TNBC patients. Mechanistically, we identified phosphodiesterase 4D (PDE4D) as a direct transcriptional target of TRPS1 and showed that TRPS1-driven PDE4D upregulation promotes paclitaxel resistance by activating cAMP–PI3K–AKT survival signaling and destabilizing microtubules. Importantly, pharmacological inhibition of PDE4D with roflumilast, an FDA-approved PDE4 inhibitor, restored cAMP signaling, suppressed AKT activation, improved microtubule stability, and resensitized TRPS1-high TNBC models to paclitaxel in vitro and in vivo. Together, these findings define the TRPS1–PDE4D axis as a previously unrecognized driver of paclitaxel resistance in TNBC, support TRPS1 as a potential predictive biomarker of treatment response, and suggest that repurposing roflumilast may represent a promising therapeutic strategy to overcome paclitaxel resistance in TRPS1-overexpressing TNBC.