Periostin Exon-21 Antibody Neutralization of Triple-Negative Breast Cancer Cell-Derived Periostin Regulates Tumor-Associated Macrophage Polarization and Angiogenesis

SIMPLE SUMMARY: Despite remarkable advances in breast cancer treatment, few strategies other than standard cytotoxic chemotherapy are available for patients with triple-negative breast cancer (TNBC) due to the lack of therapeutic target molecules. TNBC is still the most aggressive subtype, with a high risk of recurrence and metastasis within 2 years after initial treatment. Thus, there is an unmet medical need to develop new treatments for metastatic and recurrent TNBC patients. In this study we tested a new antibody, targeting extracellular periostin protein alternative splicing variants, which are induced by conventional chemotherapy or during the process of endothelial mesenchymal transition. This antibody reduced periostin-secreting TNBC in a mouse xenograft model, accompanied by a decrease in the number of M2 tumor-associated macrophages and tumor vessels. Periostin alternative splicing variants might be a specific and safe therapeutic target in patients with TNBC. ABSTRACT: Periostin (Pn) is involved in multiple processes of cancer progression. Previously, we reported that Pn expression is correlated with mesenchymal tumor markers and poor prognosis in triple-negative breast cancer (TNBC). In the TNBC xenograft model, chemotherapy increased expression of a Pn alternative splicing variant (ASV) with exon 21, and administration of the neutralizing antibody against Pn with exon 21 (Pn-21 Ab) overcame chemoresistance with a reduction in the mesenchymal cancer cell fraction. In the present study, the role of Pn ASV with exon 21 in TNBC progression has been addressed. We first established a stable cell line carrying a fluorescence-based splicing reporter. Pn-positive TNBC has higher expression of genes related to tumor-associated macrophage (TAM) recruitment and ECM-receptor interaction than Pn-negative cells. In a xenograft model, only Pn-positive cells initiated tumor formation, and the Pn-21 Ab suppressed tumor cell growth, accompanied by decreased M2 TAM polarization and the number of tumor vessels. These data suggest that cancer cell-derived Pn ASV educates TAMs and regulates angiogenesis, which in turn establishes a microenvironmental niche that is supportive of TNBC.