Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors
Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors
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DOI：
10.1158/0008-5472.can-07-5480
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发表时间：
2008-05-01
期刊：
影响因子：
11.2
通讯作者：
Lee, Eva Y-H. P.
中科院分区：
文献类型：
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作者：
Shafee, Norazizah;Smith, Christopher R.;Lee, Eva Y-H. P.
大多数brca1相关乳腺癌是基底细胞样，这与预后不良有关。利用自发性小鼠乳腺肿瘤模型，我们发现在修复过程中产生DNA断裂的铂化合物在Brca1/p53突变肿瘤中比阿霉素更有效。在每日0.5 mg/kg顺铂治疗下，80%的原发性肿瘤（n = 8）表现出完全的病理反应。在较大剂量下，100%显示完全缓解（n = 19）。然而，在铂治疗后2至3个月完全缓解后，肿瘤复发，对连续几轮治疗变得难治性。大约3.8% - 8.0%（平均5.9%）的肿瘤细胞表达正常乳腺干细胞标志物CD29(hi)24(med)，这些细胞具有致瘤性，而CD29(med)24（-/Io）和CD29(med)24（hi）细胞的致瘤性降低或非致瘤性。在部分铂反应的原发性移植中，6.6%至11.0%（平均8.8%）的肿瘤细胞是CD29(hi) 24(med)；在铂难治性继发肿瘤移植中，这些人群显著增加到16.5% ~ 29.2%（平均22.8%,P < 0.05）。此外，在顺铂存在下，难治性肿瘤细胞比原代移植源细胞具有更大的集落形成能力。在继发移植的CD29(hi)24（med）群体中，正常干细胞标志物Nanog的表达降低。在继发性耐药肿瘤群体中，Top2A的表达也下调，在一个病例中，Top2A的基因组缺失。这些研究确定了乳腺癌治疗靶向的不同癌细胞群，并暗示癌症干细胞样细胞的克隆进化和扩增是化疗耐药的潜在原因。
The majority of BRCA1-associated breast cancers are basal cell-like, which is associated with a poor outcome. Using a spontaneous mouse mammary tumor model, we show that platinum compounds, which generate DNA breaks during the repair process, are more effective than doxorubicin in Brca1/p53-mutated tumors. At 0.5 mg/kg of daily cisplatin treatment, 80% primary tumors (n = 8) show complete pathologic response. At greater dosages, 100% show complete response (n = 19). However, after 2 to 3 months of complete remission following platinum treatment, tumors relapse and become refractory to successive rounds of treatment. Approximately 3.8% to 8.0% (mean, 5.9%) of tumor cells express the normal mammary stem cell markers, CD29(hi)24(med), and these cells are tumorigenic, whereas CD29(med)24(-/Io) and CD29(med) 24(hi) cells have diminished tumorigenicity or are nontumorigenic, respectively. In partially platinum-responsive primary transplants, 6.6% to 11.0% (mean, 8.8%) tumor cells are CD29(hi) 24(med); these populations significantly increase to 16.5% to 29.2% (mean, 22.8%; P < 0.05) in platinum-refractory secondary tumor transplants. Further, refractory tumor cells have greater colony-forming ability than the primary transplant-derived cells in the presence of cisplatin. Expression of a normal stem cell marker, Nanog, is decreased in the CD29(hi)24(med) populations in the secondary transplants. Top2A expression is also down-regulated in secondary drug-resistant tumor populations and, in one case, was accompanied by genomic deletion of Top2A. These studies identify distinct cancer cell populations for therapeutic targeting in breast cancer and implicate clonal evolution and expansion of cancer stem-like cells as a potential cause of chemoresistance.