Abstract
The translation of basic research into improved therapies for breast cancer patients requires relevant preclinical models that incorporate spontaneous metastasis. We have completed a functional and molecular characterisation of a new isogenic C57BL/6 mouse model of breast cancer metastasis, comparing and contrasting it with the established BALB/c 4T1 model. Metastatic EO771.LMB tumours were derived from poorly metastatic parental EO771 mammary tumours. Functional differences were evaluated using both in vitro assays and spontaneous metastasis assays in mice. Results were compared to non-metastatic 67NR and metastatic 4T1.2 tumours of the 4T1 model. Protein and transcript levels of markers of human breast cancer molecular subtypes were measured in the four tumour lines, as well as p53 (Tp53) tumour-suppressor gene status and responses to tamoxifen in vivo and in vitro. Array-based expression profiling of whole tumours identified genes and pathways that were deregulated in metastatic tumours. EO771.LMB cells metastasised spontaneously to lung in C57BL/6 mice and displayed increased invasive capacity compared with parental EO771. By immunohistochemical assessment, EO771 and EO771.LMB were basal-like, as was the 4T1.2 tumour, whereas 67NR had a luminal phenotype. Primary tumours from all lines were negative for progesterone receptor, Erb-b2/Neu and cytokeratin 5/6, but positive for epidermal growth factor receptor (EGFR). Only 67NR displayed nuclear estrogen receptor alpha (ERα) positivity. EO771 and EO771.LMB expressed mutant p53, whereas 67NR and 4T1.2 were p53-null. Integrated molecular analysis of both the EO771/EO771.LMB and 67NR/4T1.2 pairs indicated that upregulation of matrix metalloproteinase-3 (MMP-3), parathyroid hormone-like hormone (Pthlh) and S100 calcium binding protein A8 (S100a8) and downregulation of the thrombospondin receptor (Cd36) might be causally involved in metastatic dissemination of breast cancer.
Highlights
The high mortality rate associated with advanced breast cancer is due primarily to the growth of metastases, mainly targeting liver, lung, bone and brain
In this work, the authors describe a new mouse model of metastatic breast cancer based on a spontaneous mammary tumour that arose in a C57BL/6 mouse
Integrated molecular analysis of these tumours revealed important genes – including those that encode matrix metalloproteinase3 (MMP-3) and parathyroid hormone-like hormone (Pthlh) – whose dysregulation might be causally involved in metastatic dissemination of breast cancer
Summary
The high mortality rate associated with advanced breast cancer is due primarily to the growth of metastases, mainly targeting liver, lung, bone and brain. Gene expression profiling of breast tumours has led to the identification of up to ten subtypes in humans (Curtis et al, 2012; The Cancer Genome Atlas Network, 2012; Lehmann et al, 2011; Perou et al, 2000; Sørlie et al, 2001) and many subtypes in transgenic mouse models of breast cancer (Herschkowitz et al, 2007; Pfefferle et al, 2013) These include the well-accepted luminal A, luminal B, basal-like and HER2-enriched subtypes (Herschkowitz et al, 2007; Perou et al, 2000; Sørlie et al, 2001). More relevant prognostic biomarkers and therapeutic targets are required within each of the molecular subtypes of human breast cancer, but especially for basal-like and triple-negative tumours, for which no targeted therapies currently exist
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