High Myc expression and transcription activity underlies intra-tumoral heterogeneity in triple-negative breast cancer.
High Myc expression and transcription activity underlies intra-tumoral heterogeneity in triple-negative breast cancer.
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DOI：
10.18632/oncotarget.15891
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发表时间：
2017-04-25
期刊：
影响因子：
--
通讯作者：
Lai R
中科院分区：
文献类型：
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作者：
Gupta N;Jung K;Wu C;Alshareef A;Alqahtani H;Damaraju S;Mackey JR;Ghosh S;Sabri S;Abdulkarim BS;Bigras G;Lai R
我们之前在三阴性乳腺癌（TNBC）中发现了一种新的肿瘤内二分法，基于对含有Sox2调控区-2 （SRR2）的报告细胞的差异反应，报告细胞应答（RR）比报告细胞无应答（RU）更像干细胞。利用生物信息学，我们分析了SRR2的蛋白质- dna结合基序，并确定Myc是驱动SRR2活性的潜在转录因子之一。研究发现，与RU细胞相比，Myc在RR细胞中高度表达，这支持了它的作用。RU细胞中MYC的强化表达导致SRR2活性、MYC - dna结合、表达CD44+/CD24 -的细胞比例、化疗耐药和乳腺球形成显著增加。在RR细胞中使用siRNA敲除Myc会产生相反的效果。我们还发现证据表明，RR细胞中相对较高的ERK激活有助于其Myc和干细胞样特征的高表达。使用共聚焦显微镜和患者样本，我们发现Myc和CD44在同一细胞群中存在共定位。最后，肿瘤中myc阳性细胞的高比例与较短的患者生存期显著相关。总之，抑制MAPK/ERK/Myc轴可能是消除TNBC中干细胞样细胞的有效途径。
We have previously identified a novel intra-tumoral dichotomy in triple-negative breast cancer (TNBC) based on the differential responsiveness to a reporter containing the Sox2 regulatory region-2 (SRR2), with reporter responsive (RR) cells being more stem-like than reporter unresponsive (RU) cells. Using bioinformatics, we profiled the protein-DNA binding motifs of SRR2 and identified Myc as one of the potential transcription factors driving SRR2 activity. In support of its role, Myc was found to be highly expressed in RR cells as compared to RU cells. Enforced expression of MYC in RU cells resulted in a significant increase in SRR2 activity, Myc-DNA binding, proportion of cellsexpressing CD44+/CD24–, chemoresistance and mammosphere formation. Knockdown of Myc using siRNA in RR cells led to the opposite effects. We also found evidence that the relatively high ERK activation in RR cells contributes to their high expression of Myc and stem-like features. Using confocal microscopy and patient samples, we found a co-localization between Myc and CD44 in the same cell population. Lastly, a high proportion of Myc-positive cells in tumors significantly correlated with a short patient survival. In conclusion, inhibition of the MAPK/ERK/Myc axis may be an effective approach in eliminating stem-like cells in TNBC.