Dietary energy balance modulates epithelial-to-mesenchymal transition and tumor progression in murine claudin-low and basal-like mammary tumor models.
Dietary energy balance modulates epithelial-to-mesenchymal transition and tumor progression in murine claudin-low and basal-like mammary tumor models.
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DOI：
10.1158/1940-6207.capr-12-0034
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Hursting SD
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文献类型：
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作者：
Dunlap SM;Chiao LJ;Nogueira L;Usary J;Perou CM;Varticovski L;Hursting SD
利用新型小鼠低claudin和基底样乳腺癌模型，我们验证了饮食诱导的肥胖（DIO）和卡路里限制（CR）对这些侵袭性乳腺癌亚型的进展有差异调节的假设。为了建立模型，我们鉴定了来自MMTV-Wnt-1转基因小鼠乳腺肿瘤的两种细胞系，“间充质(M)-Wnt”和“上皮(E)-Wnt”。相对于E-Wnt， M-Wnt细胞肿瘤起始细胞（TIC）富集（62% vs 2.4% cd44高/ cd24低），并且显示出增强的去荧光阳性、上皮-间质转化（EMT）标记表达、乳腺球形成能力、迁移、侵袭和致瘤性（每个参数p<0.001）。在基因表达谱中，M-Wnt和E-Wnt细胞分别与claudin-low和基底样乳腺肿瘤聚集在一起，并在原位移植到卵巢切除的C57BL/6小鼠体内时再现了这些肿瘤。为了评估能量平衡干预对肿瘤进展和EMT的影响，在M-Wnt或E-Wnt细胞原位移植前，小鼠被给予DIO、对照或CR饮食8周（每种细胞系，n=20只小鼠/饮食），并在监测肿瘤生长的同时继续饮食6周。与对照组相比，DIO增强了M-Wnt (p=0.01)，但对E-Wnt无促进作用；EMT和tic相关标志物上调，包括N-cadherin、纤维连接蛋白、TGFβ、SNAIL、FOXC2和Oct4（均p<0.05）；肿瘤内脂肪细胞增多。相反，CR抑制M-Wnt和E-Wnt肿瘤进展（p均<0.02），抑制EMT和瘤内脂肪细胞积累。因此，饮食能量平衡干预对低cludin和基底样肿瘤的EMT和进展有不同的调节作用。EMT通路成分可能是打破肥胖-乳腺癌联系的靶点，特别是在预防和/或控制tic富集亚型（如低claudin乳腺癌）方面。
Using novel murine models of claudin-low and basal-like breast cancer, we tested the hypothesis that diet-induced obesity (DIO) and calorie restriction (CR) differentially modulate progression of these aggressive breast cancer subtypes. For model development, we characterized two cell lines, “mesenchymal (M)-Wnt” and “epithelial (E)-Wnt,” derived from MMTV-Wnt-1 transgenic mouse mammary tumors. M-Wnt, relative to E-Wnt, cells were tumor-initiating cell (TIC)-enriched (62% vs 2.4% CD44high/CD24low), and displayed enhanced aldefluor-positivity, epithelial-to-mesenchymal transition (EMT) marker expression, mammosphere-forming ability, migration, invasion, and tumorigenicity (p<0.001, each parameter). M-Wnt and E-Wnt cells clustered with claudin-low and basal-like breast tumors, respectively, in gene expression profiles, and recapitulated these tumors when orthotopically transplanted into ovariectomized C57BL/6 mice. To assess the effects of energy balance interventions on tumor progression and EMT, mice were administered DIO, control or CR diets for 8 weeks before orthotopic transplantation of M-Wnt or E-Wnt cells (for each cell line, n=20 mice/diet), and continued on their diets for 6 weeks while tumor growth was monitored. Relative to control, DIO enhanced M-Wnt (p=0.01), but not E-Wnt, tumor progression; upregulated EMT- and TIC-associated markers including N-cadherin, fibronectin, TGFβ, SNAIL, FOXC2, and Oct4 (p<0.05, each); and increased intratumoral adipocytes. Conversely, CR suppressed M-Wnt and E-Wnt tumor progression (p<0.02, each) and inhibited EMT and intratumoral adipocyte accumulation. Thus dietary energy balance interventions differentially modulate EMT and progression of claudin-low and basal-like tumors. EMT pathway components may represent targets for breaking the obesity-breast cancer link, particularly for preventing and/or controlling TIC-enriched subtypes such as claudin-low breast cancer.