Loss of p16 expression is associated with the stem cell characteristics of surface markers and therapeutic resistance in estrogen receptor-negative breast cancer
Loss of p16 expression is associated with the stem cell characteristics of surface markers and therapeutic resistance in estrogen receptor-negative breast cancer
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DOI：
10.1002/ijc.26271
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发表时间：
2012-06-01
影响因子：
6.4
通讯作者：
Saya, Hideyuki
中科院分区：
文献类型：
--
作者：
Arima, Yoshimi;Hayashi, Naoki;Saya, Hideyuki
三阴性乳腺癌[TNBC，雌激素受体（ER）、孕激素受体和人表皮生长因子受体2阴性]是一种高风险的疾病，无需特异性治疗。DNA微阵列和免疫组织化学分析表明，大多数tnbc属于乳腺癌的基底样组织学亚群，其经常表现为视网膜母细胞瘤肿瘤抑制因子（Rb）失活和细胞周期蛋白依赖性激酶抑制剂p16INK4a （p16）上调。然而，在一些基底样乳腺癌细胞系中观察到p16表达下调，提示这些细胞可以根据Rb和p16的状态分为两组。我们现在发现，与干细胞样乳腺癌细胞相关的一种表型CD44+和CD24-细胞在ER-/p16-乳腺癌细胞系中比在ER-/p16+细胞系中更丰富。我们还发现，在er阴性乳腺癌细胞系的乳腺球中，p16的表达下调。在er阴性乳腺癌细胞中，通过RNA干扰去除p16增加了CD44+/CD24-细胞的百分比，并通过rb非依赖性途径增加了es样基因Nanog、Oct4和Sox2的mRNA表达。此外，p16的缺失降低了化学敏感性。因此，p16表达的缺失可能通过赋予癌症干细胞样特性来降低er阴性乳腺癌细胞对化疗的反应。与这一结论一致的是，临床样本的免疫组织化学分析表明，TNBC中p16的低表达与术前化疗耐药有关。
Triple-negative breast cancer [TNBC, which is negative for the estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2] is a high-risk form of the disease without a specific therapy. DNA microarray and immunohistochemical analyses have shown that most TNBCs fall within the basal-like histological subset of breast cancers, which frequently exhibit inactivation of the retinoblastoma tumor suppressor (Rb) and upregulation of the cyclin-dependent kinase inhibitor p16INK4a (p16). However, downregulation of p16 expression has been observed in some basal-like breast cancer cell lines, suggesting that such cells can be divided into two groups according to Rb and p16 status. We now show that cells that are CD44+ and CD24-, a phenotype associated with stem-like breast cancer cells, are more abundant in ER-/p16- breast cancer cell lines than in ER-/p16+ lines. It was also found that p16 expression was downregulated in mammospheres from an ER-negative breast cancer cell line. Depletion of p16 by RNA interference in ER-negative breast cancer cells increased the percentage of CD44+/CD24- cells and increased the expression of mRNA of the ES-like genes Nanog, Oct4, and Sox2 through an Rb-independent pathway. Furthermore, such depletion of p16 reduced chemosensitivity. The loss of p16 expression may thus reduce the response of ER-negative breast cancer cells to chemotherapy by conferring cancer stem cell-like properties. Consistent with this conclusion, immunohistochemical analysis of the clinical samples suggests that low p16 expression in TNBC is associated with resistance to preoperative chemotherapy.