Claudin 1 promotes blood-borne metastasis by modulating the Src/Ezrin signaling pathway in high-CLDN1 triple-negative breast cancer model

Abstract

ABSTRACT This study aimed to elucidate the role and mechanism of CLDN1 in regulating migration and metastasis in triple‑negative breast cancer (TNBC). In vivo, an orthotopic TNBC model was used to evaluate circulating tumor cells and lung metastasis; in vitro, cell migration, F‑actin organization, and protein expression were examined in cultured TNBC cells. CLDN1 was knocked down or overexpressed via lentiviral constructs, and Ezrin was silenced by siRNA in CLDN1‑overexpressing cells. Pharmacological targeting of CLDN1 with PDS‑0330 specifically reduced migration in MDA‑MB‑468 cells but not in MDA‑MB‑231 cells; knock-down and knock‑in experiments further confirmed that CLDN1 critically determines the migratory and metastatic capacity of TNBC cells with high CLDN1 expression. Analysis of Ezrin and its interaction with podocalyxin revealed that Ezrin significantly contributes to CLDN1‑promoted migration, and our data also indicated that CLDN1 facilitates Src signaling activation. Collectively, these findings demonstrate that in TNBC with high CLDN1 expression, CLDN1 plays a pivotal role in regulating migration and hematogenous metastasis, likely through upregulating the Src/Ezrin pathway.