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

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.

A Survey among Breast Cancer Specialists on the Low Uptake of Therapeutic Prevention with Tamoxifen or Raloxifene.

With this survey, we aimed to address the reasons why physicians are reluctant to prescribe breast cancer-preventive therapy with the selective estrogen receptor modulators (SERM) tamoxifen or raloxifene despite a strong evidence of efficacy. A self-administered 5-point Likert questionnaire was given during breast cancer meetings in Europe or sent via email to rank the importance of 10 predefined reasons for low uptake of SERMs for breast cancer therapeutic prevention. Analyses tested the associations between the stated reasons and physician characteristics such as gender, age, country of work, and specialty. Of 246 delivered questionnaires, 27 were incomplete and were excluded from analysis. Overall, there was a small variability in response scores, with a tendency for physicians to give moderate importance (score = 3) to all 10 statements. However, the top five reasons were: the expected greater preventive effectiveness of aromatase inhibitors (70.3% with score >3), difficulty applying current risk models in clinical practice (69.9%), the lack of clarity on the most appropriate physician for prevention advice (68.4%), the lack of reliable short-term biomarkers of effectiveness (67.5%), and the lack of commercial interest in therapeutic prevention (66.0%). The lack of reliable short-term biomarkers showed a tendency to discriminate between medical oncologists and other breast specialists (OR = 2.42; 95% CI, 0.93-6.25). This survey highlights the complexity of prescribing decisions among physicians in this context. Coupled with the known barriers among eligible women, these data may help to identify strategies to increase uptake of breast cancer therapeutic prevention. Cancer Prev Res; 11(1); 38-43. ©2017 AACR.