Pubertal and adult windows of susceptibility to a high animal fat diet in Trp53-null mammary tumorigenesis.
Pubertal and adult windows of susceptibility to a high animal fat diet in Trp53-null mammary tumorigenesis.
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DOI：
10.18632/oncotarget.13112
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发表时间：
2016-12-13
期刊：
影响因子：
--
通讯作者：
Haslam SZ
中科院分区：
文献类型：
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作者：
Zhu Y;Aupperlee MD;Zhao Y;Tan YS;Kirk EL;Sun X;Troester MA;Schwartz RC;Haslam SZ
绝经前乳腺癌与正常体重的动物脂肪消耗增加有关，但与超重女性无关（Farvid 等，2014）。我们之前在抗肥胖 BALB/c 小鼠中的研究结果同样表明，高饱和动物脂肪 (HFD) 饮食会促进致癌物诱导的乳腺肿瘤发生。与成人 HFD 相比，这种效应是青春期特有的。本研究确定了 HFD 对 Trp53 缺失移植 BALB/c 小鼠在青春期与成年期的影响，并研究了其增强肿瘤发生的机制。无论是青春期还是成人 HFD 都足以增加 Trp53 缺失乳腺肿瘤的发生率。青春期限制的 HFD 暴露促进肿瘤细胞增殖，增加血管生成，并增加上皮肿瘤中总巨噬细胞和 M2 巨噬细胞的募集。成人限制性接触 HFD 同样会增加增殖、血管生成、总巨噬细胞和 M2 巨噬细胞的募集，并另外减少细胞凋亡。成人HFD还增加了类似于claudin低乳腺癌的梭形细胞癌的发病率，因此Trp53缺失移植系统中的成人HFD可能是人类claudin低乳腺癌的有用模型。重要的是，Trp53-null 的这些结果以及我们之前对 DMBA 诱导的乳腺肿瘤发生的研究证明了青春期对 HFD 促进作用的敏感性窗口，表明早期饮食干预具有降低乳腺癌风险的潜力。
Premenopausal breast cancer is associated with increased animal fat consumption among normal weight, but not overweight women (Farvid et al., 2014). Our previous findings in obesity-resistant BALB/c mice similarly showed promotion of carcinogen-induced mammary tumorigenesis by a diet high in saturated animal fat (HFD). This effect was specific to pubertal versus adult HFD. This study identifies the effects of HFD during puberty versus adulthood in Trp53-null transplant BALB/c mice and investigates its mechanism of enhancing tumorigenesis. Either pubertal or adult HFD is sufficient to increase incidence of Trp53-null mammary tumors. Puberty-restricted HFD exposure promoted tumor cell proliferation, increased angiogenesis, and increased recruitment of total and M2 macrophages in epithelial tumors. Adult-restricted exposure to HFD similarly increased proliferation, angiogenesis, recruitment of total and M2 macrophages, and additionally reduced apoptosis. Adult HFD also increased incidence of spindle cell carcinomas resembling claudin-low breast cancer, and thus adult HFD in the Trp53-null transplantation system may be a useful model for human claudin low breast cancer. Importantly, these results on Trp53-null and our prior studies on DMBA-induced mammary tumorigenesis demonstrate a pubertal window of susceptibility to the promotional effects of HFD, indicating the potential of early life dietary intervention to reduce breast cancer risk.