The Characterization of Tubulointerstitial Nephritis Antigen-like 1 as a Secreted Metastasis Suppressor in Breast Cancer

Abstract

Tubulointerstitial nephritis antigen like 1 (Tinagl1) is a poorly-characterized secreted matricellular protein studied mostly in the context of development. Here, we demonstrate the role of Tinagl1 in suppressing breast cancer metastasis, in part through its dose-dependent influence on cancer cell migration and inhibition of the canonical Wnt signaling pathway activation. Serum starvation resulted in a decrease of Tinagl1 expression, suggesting that Tinagl1 is also involved in cell stress recognition pathways. Importantly, Tinagl1 expression is negatively correlated with metastatic potential of human breast and mammary tumor cells, and increased presence of Tinagl1 in vivo, either through ectopic expression of Tinagl1 in tumor cells or treatment with recombinant Tinagl1, correlate with a decrease in pulmonary metastasis. Our observation that Tinagl1 affects cellular signaling rather than morphology suggests that Tinagl1 acts as a mediator protein for signaling pathways such as Wnt with diverse downstream effects that results in metastasis suppression. We therefore propose Tinagl1 as a potential therapeutic agent as well as a metastasis biomarker.