IΚΚε cooperates with either MEK or non-canonical NF-kB driving growth of triple-negative breast cancer cells in different contexts.
IΚΚε cooperates with either MEK or non-canonical NF-kB driving growth of triple-negative breast cancer cells in different contexts.
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DOI：
10.1186/s12885-018-4507-2
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发表时间：
2018-05-25
期刊：
影响因子：
3.8
通讯作者：
Annunziata CM
中科院分区：
文献类型：
--
作者：
House CD;Grajales V;Ozaki M;Jordan E;Wubneh H;Kimble DC;James JM;Kim MK;Annunziata CM
尽管新的靶向治疗取得了成功，但转移性乳腺癌的预后很差。对于三阴性乳腺癌（TNBC）亚型，治疗选择仍然特别有限。包括NF-κB在内的几种信号通路在TNBC中发生改变，并且这种疾病的复杂性意味着多方面的通路相互作用。鉴于IKKε在乳腺癌中作为致癌基因发挥作用，我们假设IKKε调节NF-κB信号传导以控制TNBC中的多种致癌功能。利用载体表达和RNA干扰技术研究IKKε在三阴性乳腺癌细胞中的功能作用。在表达高或低水平IKKε的细胞中，结合p52 RNA干扰或MEK抑制，检查了活力、蛋白表达、NF-κB结合活性、侵袭、失巢凋亡和球体形成。该研究发现，非典型NF-κB p52水平与IKK ε成反比，并且TNBC细胞在锚定支持性、高附着条件下的生长需要IKKε和活化的MEK。这些细胞在抗锚定条件下的生长需要IKKε和活化的MEK或p52。在该模型中，IKKε和MEK合作以支持整体活力，而p52转录因子仅在低附着条件下为活力所需，强调了这些蛋白质的对比作用。这项研究阐明了IKKε在TNBC中的多种功能，并强调了NF-κB信号传导在不同生长条件下维持癌细胞存活的适应性。更好地理解NF-κB信号传导的多样性可能最终改善TNBC新型治疗方案的开发。本文的在线版本（10.1186/s12885-018-4507-2）包含补充材料，可供授权用户使用。
Metastatic breast cancer carries a poor prognosis despite the success of newly targeted therapies. Treatment options remain especially limited for the subtype of triple negative breast cancer (TNBC). Several signaling pathways, including NF-κB, are altered in TNBC, and the complexity of this disease implies multi-faceted pathway interactions. Given that IKKε behaves as an oncogene in breast cancer, we hypothesized that IKKε regulates NF-κB signaling to control diverse oncogenic functions in TNBC. Vector expression and RNA interference were used to investigate the functional role of IKKε in triple-negative breast cancer cells. Viability, protein expression, NF-κB binding activity, invasion, anoikis, and spheroid formation were examined in cells expressing high or low levels of IKKε, in conjunction with p52 RNA interference or MEK inhibition. This study found that non-canonical NF-κB p52 levels are inversely proportional to ΙΚΚε, and growth of TNBC cells in anchorage supportive, high-attachment conditions requires IKKε and activated MEK. Growth of these cells in anchorage resistant conditions requires IKKε and activated MEK or p52. In this model, IKKε and MEK cooperate to support overall viability whereas the p52 transcription factor is only required for viability in low attachment conditions, underscoring the contrasting roles of these proteins. This study illustrates the diverse functions of IKKε in TNBC and highlights the adaptability of NF-κB signaling in maintaining cancer cell survival under different growth conditions. A better understanding of the diversity of NF-κB signaling may ultimately improve the development of novel therapeutic regimens for TNBC. The online version of this article (10.1186/s12885-018-4507-2) contains supplementary material, which is available to authorized users.
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影响因子：
3.8
作者：
Barham W;Chen L;Tikhomirov O;Onishko H;Gleaves L;Stricker TP;Blackwell TS;Yull FE
通讯作者：
Yull FE
影响因子：
3.7
作者：
Nakatsu Y;Matsuoka M;Chang TH;Otsuki N;Noda M;Kimura H;Sakai K;Kato H;Takeda M;Kubota T
通讯作者：
Kubota T
影响因子：
11.5
作者：
Hoeflich, Klaus P.;O'Brien, Carol;Lackner, Mark R.
通讯作者：
Lackner, Mark R.
影响因子：
11.2
作者：
House CD;Jordan E;Hernandez L;Ozaki M;James JM;Kim M;Kruhlak MJ;Batchelor E;Elloumi F;Cam MC;Annunziata CM
通讯作者：
Annunziata CM
影响因子：
15.9
作者：
Barbie, Thanh U.;Alexe, Gabriela;Gillanders, William E.
通讯作者：
Gillanders, William E.