Selective Inhibition of Periostin Exon 21 Enhances the Efficacy of Radiation and Chemotherapy in Breast Cancer

Background: Periostin (POSTN,PN) is a matricellular protein that contributes to breast-cancer progression, epithelial–mesenchymal transition (EMT), and therapy resistance. Among its isoforms, those containing exon 21 are preferentially expressed in the tumor microenvironment and promote malignant phenotypes. Our previous work demonstrated that POSTN blockade overcame paclitaxel resistance by restricting mesenchymal-like tumor subpopulations in breast cancer, highlighting POSTN’s role in chemoresistance. Building on this finding, we developed a novel monoclonal antibody targeting POSTN exon 21 (PN-21Ab) and investigated its combination with radiation and multiple chemotherapeutic agents. In murine xenograft models, PN-21Ab was administered with radiation (9 Gy) or with doxorubicin, eribulin, vinorelbine, or 5-fluorouracil (5-FU). Tumor growth and EMT-marker expression were analyzed. Combination therapy with PN-21Ab and radiation markedly suppressed tumor growth and EMT induction compared with radiation alone (p < 0.05). PN-21Ab also potentiated the antitumor efficacy of all tested drugs without apparent toxicity. Isoform analysis revealed that POSTN variants containing exon 21 were strongly associated with tumor progression and treatment resistance. These findings demonstrate that selective inhibition of POSTN exon 21 by PN-21Ab enhances the effects of radiation and chemotherapy and may provide a broadly applicable therapeutic strategy to overcome treatment resistance in breast cancer.