2. Academic Validation
  3. TRPS1 confers paclitaxel resistance in TNBC through dual activation of the PDE4D-cAMP-AKT pathway and microtubule destabilization

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

  • Breast Cancer Res. 2026 Jan 20;28(1):47. doi: 10.1186/s13058-026-02224-9.
Xin He 1 2,  Wanting Tong 1 2,  Xinyan Chen 3,  Huifen Huang 1 2,  Na Wei 1 2,  Jiayue Ma 1 2,  Yuqiong Liu 1 2,  Yihui Ma 1 2,  Shenglei Li 1 2,  Wencai Li 1 2,  Huixiang Li 1 2,  Huayan Ren 4 5 6
Affiliations

Affiliations

  • 1 Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • 2 College of Basic Medical Sciences, Zhengzhou University, Jianshe Road 1, Erqi Ward, Zhengzhou, 450052, China.
  • 3 University of Pittsburgh, Pittsburgh, PA, USA.
  • 4 Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. [email protected].
  • 5 College of Basic Medical Sciences, Zhengzhou University, Jianshe Road 1, Erqi Ward, Zhengzhou, 450052, China. [email protected].
  • 6 University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, 15213, USA. [email protected].
PMID: 41559814 DOI: 10.1186/s13058-026-02224-9
Abstract

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.

Keywords

Chemoresistance; Microtubule dynamics; PDE4D; Roflumilast; TRPS1; Triple-negative breast cancer.

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