TIMP-2 suppresses tumor growth and metastasis in murine model of triple-negative breast cancer

Abstract

Metastasis is the primary cause of treatment failures and mortality in most cancers. Triple-negative breast cancer (TNBC) is refractory to treatment and rapidly progresses to disseminated disease. We utilized an orthotopic mouse model that molecularly and phenotypically resembles human TNBC to study the effects of exogenous, daily tissue inhibitor of metalloproteinase-2 (TIMP-2) treatment on tumor growth and metastasis. Our results demonstrated that TIMP-2 treatment maximally suppressed primary tumor growth by ~36–50% and pulmonary metastasis by >92%. Immunostaining assays confirmed disruption of the epithelial to mesenchymal transition (EMT) and promotion of vascular integrity in primary tumor tissues. Immunostaining and RNA sequencing analysis of lung tissue lysates from tumor-bearing mice identified significant changes associated with metastatic colony formation. Specifically, TIMP-2 treatment disrupts periostin localization and critical cell-signaling pathways, including canonical Wnt signaling involved in EMT, as well as PI3K signaling, which modulates proliferative and metastatic behavior through p27 phosphorylation/localization. In conclusion, our study provides evidence in support of a role for TIMP-2 in suppression of triple-negative breast cancer growth and metastasis through modulation of the epithelial to mesenchymal transition, vascular normalization, and signaling pathways associated with metastatic outgrowth. Our findings suggest that TIMP-2, a constituent of the extracellular matrix in normal tissues, may have both direct and systemic antitumor and metastasis suppressor effects, suggesting potential utility in the clinical management of breast cancer progression.

Protein Ligands in the Secretome of CD36+ Fibroblasts Induce Growth Suppression in a Subset of Breast Cancer Cell Lines

“…The ligand-receptor pairing in the CM of CD36 + FBs also indicated the enrichment of pathways involved in cytokine signaling of the immune systems, integrin cell surface interactions, insulin-like growth factor-2, and ECM organization. Table 2 shows the top four ligands that are overexpressed in the CM of CD36 + FBs, which were likely to induce growth suppression following bioinformatics analysis: • TIMP2 has been shown to suppress the growth and metastasis of triple-negative breast cancer in a murine model by disrupting Wnt and PI3K signaling [37].…”

Normalization in tumor ecosystem: Opportunities and challenges

“…(3) Vascular leakiness (or permeability) is a characteristic of an abnormal tumor vessel, so reduced permeability is considered a marker of vascular normalization (Cai et al, 2020). Vascular integrity can be strengthened by agents like tissue inhibitors of metalloproteinase‐2 (TIMP‐2), the application of which in cancers like breast is found to be promising for retarding tumor metastasis (Peeney et al, 2020). (4) Evaluation of hypoxia.…”

Immunohistochemical expression analysis of MMP-1, TIMP-2 and p53 in Barrett’s esophagus, dysplasia and esophageal adenocarcinoma

“…MMP-1 (collagenase-1) is produced by a variety of normal cells as well as numerous tumors and is associated with many malignancies; there is a negative correlation between its expression and survival [10]. TIMP-2 is a plasma protein that suppresses tumor growth and angiogenesis and inhibits epithelial-to-mesenchymal transition [11].…”