Johnstone Cameron N, Smith Yvonne E, Cao Yuan, Burrows Allan D, Cross Ryan S N, Ling Xiawei, Redvers Richard P, Doherty Judy P, Eckhardt Bedrich L, Natoli Anthony L, Restall Christina M, Lucas Erin, Pearson Helen B, Deb Siddhartha, Britt Kara L, Rizzitelli Alexandra, Li Jason, Harmey Judith H, Pouliot Normand, Anderson Robin L
Research Division, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC 3002, Australia Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, VIC 3010, Australia.
Angiogenesis and Metastasis Research, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
Dis Model Mech. 2015 Mar;8(3):237-51. doi: 10.1242/dmm.017830. Epub 2015 Jan 29.
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.
将基础研究转化为改善乳腺癌患者的治疗方法需要相关的临床前模型，这些模型要纳入自发转移的情况。我们已经完成了一种新的同基因C57BL/6乳腺癌转移小鼠模型的功能和分子特征分析，并将其与已建立的BALB/c 4T1模型进行比较和对比。转移性EO771.LMB肿瘤源自转移性较差的亲代EO771乳腺肿瘤。使用体外试验和小鼠自发转移试验评估功能差异。将结果与4T1模型的非转移性67NR和转移性4T1.2肿瘤进行比较。在这四种肿瘤细胞系中测量了人类乳腺癌分子亚型标志物的蛋白质和转录水平，以及p53（Tp53）肿瘤抑制基因状态和体内外对他莫昔芬的反应。对整个肿瘤进行基于阵列的表达谱分析，确定了在转移性肿瘤中失调的基因和通路。EO771.LMB细胞在C57BL/6小鼠中自发转移至肺部，与亲代EO771相比，其侵袭能力增强。通过免疫组织化学评估，EO771和EO771.LMB与4T1.2肿瘤一样为基底样，而67NR具有管腔表型。所有细胞系的原发性肿瘤孕激素受体、Erb-b2/Neu和细胞角蛋白5/6均为阴性，但表皮生长因子受体（EGFR）为阳性。只有67NR显示核雌激素受体α（ERα）阳性。EO771和EO771.LMB表达突变型p53，而67NR和4T1.2为p53缺失。对EO771/EO771.LMB和67NR/4T1.2这两组进行综合分子分析表明，基质金属蛋白酶-3（MMP-3）、甲状旁腺激素样激素（Pthlh）和S100钙结合蛋白A8（S100a8）的上调以及血小板反应蛋白受体（Cd36）的下调可能与乳腺癌的转移扩散有因果关系。
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