p140Cap enhances breast cancer chemosensitivity by limiting an ABCC1-enriched stem-like compartment via β-Catenin inhibition

<jats:p>Chemotherapy response in breast cancer is highly heterogeneous and influenced by tumor-intrinsic drivers of drug sensitivity, including cancer stem cell abundance. We previously reported that the scaffold protein p140Cap limits breast cancer stem cell traits and delays tumor progression. Here, we investigated the role of p140Cap in shaping sensitivity to chemotherapy in HER2-positive and triple-negative breast cancer. In preclinical and patient-derived models, p140Cap enhances chemotherapy response by increasing intracellular doxorubicin retention, DNA damage and subsequent apoptosis. Mechanistically, p140Cap constrained a doxorubicin-negative side population enriched for stem-like properties and elevated ABCC1 expression via inhibition of β-Catenin signaling. Constitutively active β-Catenin expression reversed this phenotype, whereas pharmacological inhibition of the Wnt/β-Catenin pathway with IWR-1 or LGK-974 sensitized p140Cap-deficient tumors to chemotherapy. Clinically, analyses of breast cancer cohorts and patient-derived xenograft models identify p140Cap as predictive biomarker of chemotherapy response, proposing p140Cap-guided patient stratification, dose optimization and rational combination therapies.</jats:p>