Zhu Yirong, Aupperlee Mark D, Haslam Sandra Z, Schwartz Richard C
Cell and Molecular Biology Program, Michigan State University, East Lansing, MI; Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI.
Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI; Department of Physiology, Michigan State University, East Lansing, MI.
Transl Oncol. 2017 Dec;10(6):928-935. doi: 10.1016/j.tranon.2017.09.004. Epub 2017 Oct 9.
Premenopausal breast cancer is associated with increased animal fat consumption among normal-weight but not overweight women. Our previous findings in obesity-resistant BALB/c mice showed that a diet high in saturated animal fat (HFD) promotes mammary tumorigenesis in both DMBA carcinogenesis and Trp53-null transplant models. Having made these observations in BALB/c mice, which have very modest HFD weight gain, we determined the effects of HFD in FVB mice, which gain significant weight on HFD. Three-week-old FVB mice fed a low-fat diet or HFD were subjected to 7,12-dimethylbenz[a]anthracene-induced carcinogenesis. Like BALB/c mice, HFD promoted mammary tumorigenesis. Development of tumors largely occurred prior to mice becoming obese, indicating the role of animal-derived HFD rather than resulting obesity in tumor promotion. Also similar to BALB/c mice, early-occurring adenosquamous mammary tumors were abundant among HFD-fed FVB mice. Tumors from HFD mice also had increased intra-tumor M2 macrophages. Prior to tumor development, HFD accelerated normal mammary gland development and increased mammary M2 macrophages, similarly to BALB/c mice. The promotional effects of puberty-initiated HFD on carcinogen-induced mammary cancer are thus largely weight gain-independent. Like BALB/c mice, HFD promoted adenosquamous tumors, suggesting a role for early age HFD in promoting this subtype of triple negative mammary cancer. M2 macrophage recruitment was common to both mouse strains. We speculate that a similar effect of HFD on immune function may contribute to epidemiological findings of increased breast cancer risk in young, premenopausal, normal-weight women who consume a diet high in saturated animal fat.
绝经前乳腺癌与正常体重而非超重女性的动物脂肪摄入量增加有关。我们之前在抗肥胖的BALB/c小鼠中的研究结果表明，高饱和动物脂肪饮食（HFD）在DMBA致癌和Trp53基因敲除移植模型中均能促进乳腺肿瘤发生。在体重增加非常适度的BALB/c小鼠中观察到这些现象后，我们确定了HFD对FVB小鼠的影响，FVB小鼠在HFD喂养下体重显著增加。给三周龄的FVB小鼠喂食低脂饮食或HFD，然后进行7,12-二甲基苯并[a]蒽诱导的致癌作用。与BALB/c小鼠一样，HFD促进了乳腺肿瘤发生。肿瘤的发展主要发生在小鼠肥胖之前，这表明动物来源的HFD而非由此导致的肥胖在肿瘤促进中起作用。同样与BALB/c小鼠相似，在喂食HFD的FVB小鼠中，早期发生的腺鳞癌性乳腺肿瘤很常见。HFD小鼠的肿瘤中肿瘤内M2巨噬细胞也增加。在肿瘤发生之前，HFD加速了正常乳腺发育并增加了乳腺M2巨噬细胞，这与BALB/c小鼠相似。因此，青春期开始的HFD对致癌物诱导的乳腺癌的促进作用在很大程度上与体重增加无关。与BALB/c小鼠一样，HFD促进了腺鳞癌肿瘤的发生，这表明早期摄入HFD在促进这种三阴性乳腺癌亚型中起作用。M2巨噬细胞的募集在两种小鼠品系中都很常见。我们推测，HFD对免疫功能的类似作用可能有助于解释在摄入高饱和动物脂肪饮食的年轻、绝经前、正常体重女性中乳腺癌风险增加的流行病学发现。
