Regulation of miRNA-29c and its downstream pathways in preneoplastic progression of triple-negative breast cancer.
Regulation of miRNA-29c and its downstream pathways in preneoplastic progression of triple-negative breast cancer.
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DOI：
10.18632/oncotarget.14902
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发表时间：
2017-03-21
期刊：
影响因子：
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通讯作者：
Bedrosian I
中科院分区：
文献类型：
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作者：
Bhardwaj A;Singh H;Rajapakshe K;Tachibana K;Ganesan N;Pan Y;Gunaratne PH;Coarfa C;Bedrosian I
对于三阴性乳腺癌（TNBC）的早期分子驱动因素了解甚少，这使得识别高危女性和开发靶向预防治疗面临重大挑战。通过对基于TNBC细胞系的乳腺癌进展模型进行测序，我们发现miRNA-29c在TNBC肿瘤发生过程中逐渐丢失。为了支持miRNA-29c的肿瘤抑制作用，我们发现miRNA-29c的低水平预示着患者的总体生存期较差，相反，miRNA-29c在肿瘤前细胞模型中的异位表达会抑制生长。miRNA-29c通过直接结合和调控tgfb诱导因子同源盒2 （TGIF2）、camp响应元件结合蛋白5 （CREB5）和V-Akt小鼠胸腺瘤病毒致癌基因同源物3 （AKT3）发挥其生长抑制作用。miRNA-29c对这些基因靶点的调控似乎与功能相关，因为TGIF2、CREB5和AKT3能够挽救肿瘤前细胞中miRNA-29c异位表达引起的细胞增殖和集落形成的抑制。AKT3是一种已知的与乳腺癌相关的致癌基因，作为原理的证明，我们发现抑制AKT3上游蛋白磷酸肌肽3-激酶（PI3K）活性可以抑制TNBC肿瘤前细胞的增殖。我们通过研究miRNA-29c的调控，探索了预防TNBC的其他机会，并确定了DNA甲基化在TNBC肿瘤发生过程中抑制miRNA-29c的作用。与这些观察结果一致，我们发现5 - aza-胞苷可以缓解miRNA-29c的抑制。总之，这些结果表明，miRNA-29c缺失在TNBC的早期发展中起着关键作用。
Little is understood about the early molecular drivers of triple-negative breast cancer (TNBC), making the identification of women at risk and development of targeted therapy for prevention significant challenges. By sequencing a TNBC cell line-based breast cancer progression model we have found that miRNA-29c is progressively lost during TNBC tumorigenesis. In support of the tumor suppressive role of miRNA 29c, we found that low levels predict poor overall patient survival and, conversely, that ectopic expression of miRNA-29c in preneoplastic cell models inhibits growth. miRNA-29c exerts its growth inhibitory effects through direct binding and regulation of TGFB-induced factor homeobox 2 (TGIF2), CAMP-responsive element binding protein 5 (CREB5), and V-Akt murine thymoma viral oncogene homolog 3 (AKT3). miRNA-29c regulation of these gene targets seems to be functionally relevant, as TGIF2, CREB5, and AKT3 were able to rescue the inhibition of cell proliferation and colony formation caused by ectopic expression of miRNA-29c in preneoplastic cells. AKT3 is an oncogene of known relevance in breast cancer, and as a proof of principle we show that inhibition of phosphoinositide 3-kinase (PI3K) activity, a protein upstream of AKT3, suppressed proliferation in TNBC preneoplastic cells. We explored additional opportunities for prevention of TNBC by studying the regulation of miRNA-29c and identified DNA methylation to have a role in the inhibition of miRNA-29c during TNBC tumorigenesis. Consistent with these observations, we found 5 aza-cytadine to relieve the suppression of miRNA-29c. Together, these results demonstrate that miRNA-29c loss plays a key role in the early development of TNBC.