Docetaxel treatment upregulates estrogen receptor expression in triple negative breast cancer cells via activating arachidonic acid pathway

Triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer, accounts for approximately 15% of all cases. TNBC remains challenging due to a lack of effective treatment strategies, which significantly impacts patient survival outcomes. This study investigates a novel combination therapy using Docetaxel, a microtubule depolymerization inhibitor, and Tamoxifen, an estrogen receptor (ER) antagonist, targeting TNBC. Synergistic effects of Docetaxel with Tamoxifen in TNBC cells were analyzed at SynergyFinder. Their anti-tumor growth effects were determined in vivo using both nude mice and Balb/c mice. RNA-Seq was conducted to analyze the pathways altered by Docetaxel in TNBC cells. We demonstrate that Docetaxel sensitizes TNBC cells to Tamoxifen, despite their typical ER-negative status. Here, we reveal that Docetaxel activates the arachidonic acid signaling pathway, leading to increased prostaglandin E2 (PGE2) production and subsequent upregulation of c-Jun phosphorylation, which in turn induces ESR1 expression. This ERα induction enables Tamoxifen to effectively inhibit TNBC cell proliferation. Given the clinical availability of both drugs, our findings propose a promising, translationally feasible combination strategy to address the therapeutic limitations of TNBC, offering a novel approach to improve outcomes for this high-risk patient population.