Rhophilin‐associated tail protein 1 promotes migration and metastasis in triple negative breast cancer via activation of RhoA

Abstract

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with high motile and invasive capacity that contributes to metastasis. Understanding the mechanisms for the motility of TNBC might provide novel targetable vulnerabilities of the tumors. Herein, we find that Rhophilin-associated tail protein 1 (ROPN1) is selectively overexpressed in human TNBC cell lines and tissues. Overexpression of ROPN1 promotes, while silencing of ROPN1 inhibits the robust migration, invasion, and in vivo metastasis of TNBC cells. Moreover, we find that ROPN1 activates RhoA signaling via rhophilin-1 (RHPN1), leading to enhanced actin stress fibers formation in TNBC cells. RhoA signaling is demonstrated to be essential for ROPN1mediated migration and metastasis of TNBC cells. Finally, we find that high levels of ROPN1 are significantly associated distant metastasis and predicted poor prognosis in patients with breast cancer. These findings reveal a novel mechanism for the high motility and metastasis of TNBC cells, suggesting that ROPN1 might be a potential prognostic marker and therapeutic target.

TCR-engineered T-cells directed against Ropporin-1 constitute a safe and effective treatment for triple-negative breast cancer in near-clinical models

“…The striking abundance and homogeneity of ROPN1/B in TNBC likely limit the risk of tumor recurrence following ACT since it is reported that outgrowth of antigen-negative tumor cell clones is generally a consequence of low and heterogeneous expression of target antigens within tumors [48][49][50] . Notably, a recent report highlighted that ROPN1 may act as an oncogene and drive metastasis formation in vivo and demonstrated an inverse correlation between ROPN1 expression and survival of TNBC patients 51 , further highlighting the therapeutic value of ROPN1 as a target for ACT.…”

Production and Immunological Characterization of scFv Specific to Epitope of Opisthorchis viverrini Rhophilin-Associated Tail Protein 1-like (OvROPN1L)

“…In mammals, Rhophilin-1 and its orthologues contain the N-terminal domain, ROPN1, which interacts with A-kinase anchor protein 3 (AKAP3) in both GDP- and GTP-bound RhoA in vitro. ROPN1 binding regulates the actin cytoskeleton by interacting with various downstream molecules [ 31 , 32 ]. Its N-terminal domain is interesting since it is found in only a few proteins [ 28 , 33 ].…”