Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells.
Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells.
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DOI：
10.1158/1078-0432.ccr-09-2937
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发表时间：
2010-05-01
期刊：
影响因子：
--
通讯作者：
Sun D
中科院分区：
文献类型：
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作者：
Li Y;Zhang T;Korkaya H;Liu S;Lee HF;Newman B;Yu Y;Clouthier SG;Schwartz SJ;Wicha MS;Sun D
乳腺癌中癌症干细胞（CSC）的存在对癌症预防具有深远的意义。在这项研究中，我们评估了萝卜硫素，一种来自西兰花/西兰花芽的天然化合物，其抑制乳腺CSC的功效及其潜在机制。采用Aldefluor法和乳腺球形成法检测莱菔硫烷对体外培养的乳腺CSCs的影响。采用NOD/SCID异种移植模型来确定萝卜硫素是否可以在体内靶向乳腺CSC，如通过Aldefluor测定和在第二代小鼠中细胞再植入后的肿瘤生长所评估的。利用Western blotting分析和β-catenin报告基因分析研究其可能的机制。莱菔硫烷（1~5 μM）可使人乳腺癌细胞中乙醛脱氢酶（ALDH）阳性细胞数减少65%~80%（P < 0.01），并使乳腺癌原代细胞球的大小和数量分别减少8~125倍和45%~75%（P < 0.01）。每天注射50 mg/kg莱菔硫烷两周，使NOD/SCID异种移植肿瘤中ALDH阳性细胞减少50%以上（P = 0.003）。莱菔硫烷在体内消除乳腺CSC，从而在将原代肿瘤细胞重新植入到第二代小鼠中后消除肿瘤生长（P < 0.01）。Western blotting分析和β-catenin报告基因检测结果表明，萝卜硫素下调Wnt/β-catenin自我更新途径。萝卜硫素抑制乳腺CSC并下调Wnt/β-catenin自我更新途径。这些发现支持使用萝卜硫素化学预防乳腺癌干细胞，并保证进一步的临床评价。
The existence of cancer stem cells (CSCs) in breast cancer has profound implications for cancer prevention. In this study, we evaluated sulforaphane, a natural compound derived from broccoli/broccoli sprouts, for its efficacy to inhibit breast CSCs and its potential mechanism. Aldefluor assay and mammosphere formation assay were used to evaluate the effect of sulforaphane on breast CSCs in vitro. A NOD/SCID xenograft model was employed to determine whether sulforaphane could target breast CSCs in vivo, as assessed by Aldefluor assay and tumor growth upon cell re-implantation in secondary mice. The potential mechanism was investigated utilizing Western blotting analysis and β-catenin reporter assay. Sulforaphane (1~5 μM) decreased aldehyde dehydrogenase (ALDH)-positive cell population by 65%~80% in human breast cancer cells (P < 0.01), and reduced the size and number of primary mammospheres by 8~125-fold and 45%~75% (P < 0.01), respectively. Daily injection with 50 mg/kg sulforaphane for two weeks reduced ALDH-positive cells by more than 50% in NOD/SCID xenograft tumors (P = 0.003). Sulforaphane eliminated breast CSCs in vivo, thereby abrogating tumor growth after re-implantation of primary tumor cells into the secondary mice (P < 0.01). Western blotting analysis and β-catenin reporter assay showed that sulforaphane down-regulated Wnt/β-catenin self-renewal pathway. Sulforaphane inhibits breast CSCs and down-regulates Wnt/β-catenin self-renewal pathway. These findings support the use of sulforaphane for chemoprevention of breast cancer stem cells and warrant further clinical evaluation.