Functional and genomic characterization of a xenograft model system for the study of metastasis in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) represents 10-20% of all human ductal adenocarcinomas and has a poor prognosis relative to other subtypes. Hence, new molecular targets for therapeutic intervention are necessary. Analyses of panels of human or mouse cancer lines derived from the same individual that differ in their cellular phenotypes but not in genetic background have been instrumental in defining the molecular players that drive the various hallmarks of cancer. To determine the molecular regulators of metastasis in TNBC, we completed a rigorous in vitro and in vivo characterisation of four populations of the MDA-MB-231 human breast cancer line ranging in aggressiveness from non-metastatic to spontaneously metastatic to lung, liver, spleen and lymph node. Single nucleotide polymorphism (SNP) array analyses and genome-wide mRNA expression profiles of tumour cells isolated from orthotopic mammary xenografts were compared between the four lines to define both cell autonomous pathways and genes associated with metastatic proclivity. Gene set enrichment analysis (GSEA) demonstrated an unexpected association between both ribosome biogenesis and mRNA metabolism and metastatic capacity. Differentially expressed genes or families of related genes were allocated to one of four categories, associated with either metastatic initiation (e.g. CTSC, ENG, BMP2), metastatic virulence (e.g. ADAMTS1, TIE1), metastatic suppression (e.g. CST1, CST2, CST4, CST6, SCNNA1, BMP4) or metastatic avirulence (e.g. CD74). Collectively, this model system based on MDA-MB-231 cells should be useful for the assessment of gene function in the metastatic cascade and also for the testing of novel experimental therapeutics for the treatment of TNBC.

Copy Number Variation in Triple Negative Breast Cancer Samples Associated with Lymph Node Metastasis

“…According to the enrichment scores, "production of molecular mediator of immune response", "antigen binding", "immunoglobulin production", "complement activation" and "regulation of protein activation cascade" were the most enriched GO terms (Table S6.a) and "ribosome biogenesis in eukaryotes" was the most enriched pathway from the list of genes contained within the ampli ed regions (Table S6.b). In concordance with this nding, upregulation of "gene networks related to ribosome biogenesis" has previously been demonstrated in the MDA-MB-231 TNBC cell line (31).The list of genes overlapping the deleted regions, were highly enriched in GO terms such as "neuron differentiation", "Cardiac ventricle morphogenesis", "cardiac chamber morphogenesis", "system development" and "regulation of hormone levels" (Table S6.c). No pathways were signi cantly enriched in the list of deleted genes.…”

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

“…We now present the differential features of two preclinically relevant spontaneously metastatic TNBC mouse models. First, the well‐established 4T1 model developed in an immunocompetent (BALB/c) background (representing the murine disease) and second, the MDA‐MB‐231‐Luc model established in immunodeficient (NOD/SCID) background (representing the human disease, and more specifically, the mesenchymal stem‐like subtype).…”

“…Within this study, we carried out a broad and detailed characterization of disease progression in each model and assessed for functional biomarkers, key metabolites and differential cytokines considered crucial for prognosis. Furthermore, we analyzed the suitability for the application of preclinical models in the development/translation of advanced therapeutics for TNBC treatment, as features such as the enhanced permeability and retention (EPR) effect have also been explored …”

“…Furthermore, we analyzed the suitability for the application of preclinical models in the development/translation of advanced therapeutics for TNBC treatment, as features such as the enhanced permeability and retention (EPR) effect have also been explored. 6…”

ceRNA Network Development and Tumour-infiltrating Immune Cell Analysis in Metastatic Breast Cancer of Bone

“…The process of bone metastasis is complex and has multiple stages. It requires the separation of breast cancer cells from the primary tumour site, transport to the bone via blood or lymph, and survival and proliferation in the target bone tissue [6][7][8]. Genomics research has shown that every step of metastasis is related to a series of sub-events.…”