Nidogen-1 suppresses cell proliferation, migration, and glycolysis via integrin β1-mediated HIF-1α downregulation in triple-negative breast cancer

Abstract

Nidogen-1 (NID1) is a secreted glycoprotein widely distributed in basement membranes. NID1 interacts with extracellular matrix proteins such as collagen and laminin and has been implicated in the progression of various cancers. However, study on the role of NID1 in breast cancer is scarce and inconsistent. In this work, we found that the expression of NID1 is significantly lower in breast cancer tissue than in normal tissue. In addition, NID1 expression correlated negatively with a poor prognosis for breast cancer patients. Based on those findings, we speculated that NID1 might act as a cancer suppressor in breast cancer. To investigate the role of NID1 in breast cancer, we constructed NID1-overexpressing cell lines. NID1 overexpression decreased breast cancer cell proliferation, migration, and in vivo tumor growth. Moreover, glucose metabolism, which is known to enhance cancer cell proliferation and migration, was also decreased by NID1 overexpression. Mechanistically, NID1 overexpression downregulated hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression at the transcription level. Furthermore, we found that NID1 reduced integrin beta 1 stability and downregulated the transcription of HIF-1 alpha through the FAK/Src/NF-kappa B p65 signaling axis, which is downstream of integrin beta 1. Together, the results of this study demonstrate the tumor suppressive role of NID1 in triple-negative breast cancer.