Upregulation of lipogenesis is a hallmark of cancer and blocking the lipogenic pathway is known to cause tumor cell death by apoptosis. However, the exact role of lipogenesis in tumor initiation is as yet poorly understood. We examined the expression profile of key lipogenic genes in clinical samples of ductal carcinoma in situ (DCIS) of breast cancer and found that these genes were significantly upregulated in DCIS. We also isolated cancer stem-like cells (CSCs) from DCIS.com cell line using cell surface markers (CS24(-)CD44(+)ESA(+)) and found that this cell population has significantly higher tumor-initiating ability to generate DCIS compared with the non-stem-like population. Furthermore, the CSCs showed significantly higher level of expression of all lipogenic genes than the counterpart population from non-tumorigenic breast cancer cell line, MCF10A. Importantly, ectopic expression of SREBP1, the master regulator of lipogenic genes, in MCF10A significantly enhanced lipogenesis in stem-like cells and promoted cell growth as well as mammosphere formation. Moreover, SREBP1 expression significantly increased the ability of cell survival of CSCs from MCF10AT, another cell line that is capable of generating DCIS, in mouse and in cell culture. These results indicate that upregulation of lipogenesis is a pre-requisite for DCIS formation by endowing the ability of cell survival. We have also shown that resveratrol was capable of blocking the lipogenic gene expression in CSCs and significantly suppressed their ability to generate DCIS in animals, which provides us with a strong rationale to use this agent for chemoprevention against DCIS.

译文

:脂肪生成的上调是癌症的标志,已知阻断脂肪生成途径会通过凋亡导致肿瘤细胞死亡。然而,尚不清楚脂肪生成在肿瘤起始中的确切作用。我们检查了乳腺导管原位癌(DCIS)临床样品中关键脂肪形成基因的表达谱,发现这些基因在DCIS中显着上调。我们还使用细胞表面标记(CS24(-)CD44()ESA())从DCIS.com细胞系中分离了癌干样细胞(CSC),发现与该细胞群相比,该细胞群具有更高的产生DCIS的肿瘤启动能力与非茎状种群。此外,CSCs显示所有脂肪形成基因的表达水平均高于非致瘤性乳腺癌细胞系MCF10A的对应群体。重要的是,MCF10A中异源表达的主调节因子SREBP1在MCF10A中的异位表达显着增强了干样细胞的脂肪生成,并促进了细胞生长以及乳球形成。此外,SREBP1表达显着提高了来自MCF10AT的CSC在小鼠和细胞培养物中的细胞存活能力,MCF10AT是另一种能够产生DCIS的细胞系。这些结果表明,通过赋予细胞存活能力,脂肪生成的上调是DCIS形成的先决条件。我们还显示白藜芦醇能够阻断CSC中脂肪基因的表达,并显着抑制其在动物体内生成DCIS的能力,这为我们提供了使用这种药物化学预防DCIS的强大理由。

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