Department of Preventive Medicine, Mount Sinai School of Medicine, Box 1057, New York, NY 10029, USA.
Clin Exp Metastasis. 2010 Feb;27(2):107-16. doi: 10.1007/s10585-009-9302-7. Epub 2010 Feb 12.
Metastasis virulence, a significant contributor to breast cancer prognosis, is influenced by environmental factors like diet. We previously demonstrated in an F2 mouse population generated from a cross between the M16i polygenic obese and MMTV-PyMT mammary cancer models that high fat diet (HFD) decreases mammary cancer latency and increases pulmonary metastases compared to a matched control diet (MCD). Genetic analysis detected eight modifier loci for pulmonary metastasis, and diet significantly interacted with all eight loci. Here, gene expression microarray analysis was performed on mammary cancers from these mice. Despite the substantial dietary impact on metastasis and its interaction with metastasis modifiers, HFD significantly altered the expression of only five genes in mammary tumors; four of which, including serum amyloid A (Saa), are downstream of the tumor suppressor PTEN. Conversely, HFD altered the expression of 211 hepatic genes in a set of tumor free F2 control mice. Independent of diet, pulmonary metastasis virulence correlates with mammary tumor expression of genes involved in endocrine cancers, inflammation, angiogenesis, and invasion. The most significant virulence-associated network harbored genes also found in human adipose or mammary tissue, and contained upregulated Vegfa as a central node. Additionally, expression of Btn1a1, a gene physically located near a putative cis-acting eQTL on chromosome 13 and one of the metastasis modifiers, correlates with metastasis virulence. These data support the existence of diet-dependent and independent cancer modifier networks underlying differential susceptibility to mammary cancer metastasis and suggest that diet influences cancer metastasis virulence through tumor autonomous and non-autonomous mechanisms.
转移毒力是乳腺癌预后的一个重要影响因素，受饮食等环境因素的影响。我们之前在 M16i 多基因肥胖和 MMTV-PyMT 乳腺肿瘤模型杂交产生的 F2 小鼠群体中进行的研究表明，高脂肪饮食（HFD）与匹配的对照饮食（MCD）相比，可降低乳腺肿瘤潜伏期并增加肺转移。遗传分析检测到 8 个肺转移修饰基因座，饮食与所有 8 个基因座均显著相互作用。在此，对这些小鼠的乳腺肿瘤进行了基因表达微阵列分析。尽管饮食对转移有很大影响，并与转移修饰基因相互作用，但 HFD 仅显著改变了乳腺肿瘤中 5 个基因的表达；其中包括血清淀粉样蛋白 A (Saa)，是肿瘤抑制基因 PTEN 的下游基因。相反，HFD 改变了一组无肿瘤 F2 对照小鼠肝脏中 211 个基因的表达。独立于饮食，肺转移毒力与乳腺肿瘤中参与内分泌癌、炎症、血管生成和侵袭的基因表达相关。与毒力相关的最重要网络还包含了在人类脂肪或乳腺组织中发现的基因，并且包含上调的 Vegfa 作为中心节点。此外，Btn1a1 基因的表达，该基因位于 13 号染色体上一个假定顺式作用 eQTL 附近，是一个转移修饰基因，与转移毒力相关。这些数据支持存在饮食依赖和独立的癌症修饰基因网络，这些网络是导致乳腺肿瘤转移易感性差异的基础，并表明饮食通过肿瘤自主和非自主机制影响癌症转移毒力。
