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

Carcinogenesis. 2020 May 14;41(3):313-325. doi: 10.1093/carcin/bgz172.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Carcinogenesis / genetics*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics*
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Humans
  • Neoplasm Metastasis
  • Phosphatidylinositol 3-Kinases
  • Sequence Analysis, RNA
  • Tissue Inhibitor of Metalloproteinase-2 / genetics*
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / pathology
  • Wnt Signaling Pathway / genetics
  • Xenograft Model Antitumor Assays

Substances

  • Timp2 protein, mouse
  • Tissue Inhibitor of Metalloproteinase-2