ADA3 regulates normal and tumor mammary epithelial cell proliferation through c-MYC.
ADA3 regulates normal and tumor mammary epithelial cell proliferation through c-MYC.
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DOI：
10.1186/s13058-016-0770-9
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发表时间：
2016-11-16
期刊：
影响因子：
--
通讯作者：
Band V
中科院分区：
文献类型：
--
作者：
Griffin NI;Sharma G;Zhao X;Mirza S;Srivastava S;Dave BJ;Aleskandarany M;Rakha E;Mohibi S;Band H;Band V
我们已经确定了ADA 3作为雌激素受体（ER）的共激活剂的关键作用，以及其在细胞周期进程中的作用。此外，我们发现ADA 3在乳腺上皮和ER+中主要是细胞核，但在ER-乳腺癌中是细胞质，后者与较差的存活率相关。然而，细胞核ADA 3在人乳腺上皮细胞（hMEC）和ER+乳腺癌细胞中的作用，以及ADA 3表达与ER+乳腺癌患者预后和生存率相关的重要性仍然没有得到表征。我们在hMEC或ER+乳腺癌细胞中过表达ADA 3，并评估对细胞增殖的影响。分析ADA 3的表达，然后将其与各种预后标志物的表达以及乳腺癌患者的生存相关。ADA 3在ER-hMEC以及ER+乳腺癌细胞系中的过表达增强了细胞增殖。这些细胞显示细胞周期蛋白B和c-MYC增加，p27降低和SKP 2水平增加。这伴随着早期反应基因c-FOS、EGR 1和c-MYC的mRNA水平增加。乳腺癌组织标本的分析显示ADA 3核表达与c-MYC表达显著相关。细胞核ADA 3和c-MYC的表达与肿瘤分级、核分裂、多形性、NPI、ER/PR、Ki 67和p27的表达密切相关。重要的是，在ER+病例中，核ADA 3和c-MYC的表达也与Ki 67和p27表达显著相关。对4组整体以及ER+患者的单变量Kaplan Meier分析显示，c-MYC和ADA 3组合表型显示出显著不同的乳腺癌特异性生存率，其中c-MYC-高和ADA 3-低亚组的结局最差。在整个队列和ER+亚组中使用多变量分析，ADA 3和c-MYC表达与患者结局的显著相关性与肿瘤分级、分期和大小以及ER状态无关。ADA 3过表达增强细胞增殖，这与c-MYC表达增加有关。关于ADA 3/c-MYC的表达模式可以将患者分为四个显著不同的亚组，c-MYC高和ADA 3低状态独立地预测患者的生存率差。本文的在线版本（doi：10.1186/s13058-016-0770-9）包含补充材料，可供授权用户使用。
We have established the critical role of ADA3 as a coactivator of estrogen receptor (ER), as well as its role in cell cycle progression. Furthermore, we showed that ADA3 is predominantly nuclear in mammary epithelium, and in ER+, but is cytoplasmic in ER- breast cancers, the latter correlating with poor survival. However, the role of nuclear ADA3 in human mammary epithelial cells (hMECs), and in ER+ breast cancer cells, as well as the importance of ADA3 expression in relation to patient prognosis and survival in ER+ breast cancer have remained uncharacterized. We overexpressed ADA3 in hMECs or in ER+ breast cancer cells and assessed the effect on cell proliferation. The expression of ADA3 was analyzed then correlated with the expression of various prognostic markers, as well as survival of breast cancer patients. Overexpression of ADA3 in ER- hMECs as well as in ER+ breast cancer cell lines enhanced cell proliferation. These cells showed increased cyclin B and c-MYC, decreased p27 and increased SKP2 levels. This was accompanied by increased mRNA levels of early response genes c-FOS, EGR1, and c-MYC. Analysis of breast cancer tissue specimens showed a significant correlation of ADA3 nuclear expression with c-MYC expression. Furthermore, nuclear ADA3 and c-MYC expression together showed significant correlation with tumor grade, mitosis, pleomorphism, NPI, ER/PR status, Ki67 and p27 expression. Importantly, within ER+ cases, expression of nuclear ADA3 and c-MYC also significantly correlated with Ki67 and p27 expression. Univariate Kaplan Meier analysis of four groups in the whole, as well as the ER+ patients showed that c-MYC and ADA3 combinatorial phenotypes showed significantly different breast cancer specific survival with c-MYC-high and ADA3-Low subgroup had the worst outcome. Using multivariate analyses within the whole cohort and the ER+ subgroups, the significant association of ADA3 and c-MYC expression with patients’ outcome was independent of tumor grade, stage and size, and ER status. ADA3 overexpression enhances cell proliferation that is associated with increased expression of c-MYC. Expression patterns with respect to ADA3/c-MYC can divide patients into four significantly different subgroups, with c-MYC High and ADA3 Low status independently predicting poor survival in patients. The online version of this article (doi:10.1186/s13058-016-0770-9) contains supplementary material, which is available to authorized users.
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11.2
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