Differential optineurin expression controls TGFβ signaling and is a key determinant for metastasis of triple negative breast cancer

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to its aggressive characteristics and low response to the existing clinical therapies. Distant metastasis is the main cause of death of TNBC patients. Better understanding of the mechanisms underlying TNBC metastasis may lead to new strategies of early diagnosis and more efficient treatment. In our study, we uncovered that the autophagy receptor optineurin (OPTN) plays an unexpected role in TNBC metastasis. Data mining of publicly available data bases revealed that the mRNA level of OPTN in TNBC patients positively correlates with relapse free and distance metastasis free survival. Importantly, in vitro and in vivo models demonstrated that OPTN suppresses TNBC metastasis. Mechanistically, OPTN inhibited the pro-oncogenic transforming growth factor-β (TGFβ) signaling in TNBC cells by interacting with TGFβ type I receptor (TβRI) and promoting its ubiquitination for degradation. Consistent with our experimental findings, the clinical TNBC samples displayed a negative correlation between OPTN mRNA expression and TGFβ gene response signature and expression of proto-typic TGFβ target genes. Altogether, our study demonstrates that OPTN is a negative regulator for TGFβ receptor/SMAD signaling and suppresses metastasis in TNBC.