Characterization of triple‐negative breast cancer preclinical models provides functional evidence of metastatic progression

Abstract

Triple‐negative breast cancer (TNBC), an aggressive, metastatic and recurrent breast cancer (BC) subtype, currently suffers from a lack of adequately described spontaneously metastatic preclinical models that faithfully reproduce the clinical scenario. We describe two preclinical spontaneously metastatic TNBC orthotopic murine models for the development of advanced therapeutics: an immunodeficient human MDA‐MB‐231‐Luc model and an immunocompetent mouse 4T1 model. Furthermore, we provide a broad range of multifactorial analysis for both models that could provide relevant information for the development of new therapies and diagnostic tools. Our comparisons uncovered differential growth rates, stromal arrangements and metabolic profiles in primary tumors, and the presence of cancer‐associated adipocyte infiltration in the MDA‐MB‐231‐Luc model. Histopathological studies highlighted the more rapid metastatic spread to the lungs in the 4T1 model following a lymphatic route, while we observed both homogeneous (MDA‐MB‐231‐Luc) and heterogeneous (4T1) metastatic spread to axillary lymph nodes. We encountered unique metabolomic signatures in each model, including crucial amino acids and cell membrane components. Hematological analysis demonstrated severe leukemoid and lymphoid reactions in the 4T1 model with the partial reestablishment of immune responses in the immunocompromised MDA‐MB‐231‐Luc model. Additionally, we discovered β‐immunoglobulinemia and increased basal levels of G‐CSF correlating with a metastatic switch, with G‐CSF also promoting extramedullary hematopoiesis (both models) and causing hepatosplenomegaly (4T1 model). Overall, we believe that the characterization of these preclinical models will foster the development of advanced therapeutic strategies for TNBC treatment, especially for the treatment of patients presenting both, primary tumors and metastatic spread.

Expression pattern analysis and drug differential sensitivity of cancer-associated fibroblasts in triple-negative breast cancer

“…Primary 4T1 tumors exhibit typical stromal progression with inner necrotic region development. At present, 4T1 tumor tissue is divided into three regions: proliferative region, transition border, and necrotic core [ 25 ]. According to the degree of fibrosis, the tumors were divided into pre-fibrotic region ( Fig.…”

Co‐Delivery of Paclitaxel and Interleukin‐12 Regulating Tumor Microenvironment for Cancer Immunochemotherapy

“…The growth and metastasis characteristics of 4T1 cells in BALB/c mice are with similar character to those of triple‐negative breast cancer in human, which can easily metastasize to the lung. [ 20 ] Therefore, we further studied the metastatic inhibition of PTX/IL‐12@TSNPs in a 4T1 orthotopic breast cancer model ( Figure A). The number of nodules on the surface of lung tissue is a key indicator for evaluating lung metastasis of cancer cells.…”

Pygenic Acid A (PA) Sensitizes Metastatic Breast Cancer Cells to Anoikis and Inhibits Metastasis In Vivo

“…After screening of thousand natural compounds for their ability to sensitize metastatic breast cancer cells to anoikis, we found PA candidates for inducing the apoptosis of cells under suspension conditions ( Figure 1 ). Here, we investigated whether PA has anti-metastatic effects using the metastatic triple negative breast cancer cell lines, MDA-MB-231 and 4T1, which are human and mouse breast cancer cell lines, respectively [ 11 ]. First, we evaluated the effect of PA on cell growth using the IncuCyte™ systems.…”