Soluble-E-cadherin activates HER and IAP family members in HER2+ and TNBC human breast cancers.
Soluble-E-cadherin activates HER and IAP family members in HER2+ and TNBC human breast cancers.
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DOI：
10.1002/mc.22048
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发表时间：
2014-11
影响因子：
4.6
通讯作者：
Ma, Li
中科院分区：
文献类型：
--
作者：
Brouxhon, Sabine M.;Kyrkanides, Stephanos;Teng, Xiaofei;O'Banion, M. Kerry;Clarke, Robert;Byers, Stephen;Ma, Li
最近的文献表明，sEcad具有促癌作用，可能作为人表皮生长因子家族的配体。在这里，我们发现sEcad是一种新的药物靶向候选蛋白，因为它在人和小鼠HER2阳性（HER2+）乳腺肿瘤、MMTV-PyMT体液和人类细胞培养系统中增加。在机制上，我们发现内源性sEcad和较小程度上膜结合的E-cadherin在人和MMTV-PyMT小鼠HER2+肿瘤中与HER1、HER2和HER3相关，在三阴性乳腺癌（TNBC）标本中与HER1相关。此外，在HER2+ MCF-7、SKBR3和HER2阴性MDA-MB-231 TNBC细胞中加入外源性重组人E-cadherin/Fc嵌合蛋白（recad /Fc; sEcad），可导致sEcad- her受体家族相互作用，激活HER1-4和下游促生存信号，包括MAPK-PI3K/Akt/mTOR通路和IAP家族成员。最后，我们证明了sEcad通过HER信号传导发挥促癌作用，并与HER配体EGF一起作用，促进HER2+乳腺癌的增殖和迁移，以及TNBC的侵袭。由于sEcad关联并激活了肿瘤用于生长和生存的许多致癌途径，并且患者的血清水平与临床反应相关，这表明针对sEcad的靶向治疗与其他治疗方法联合可能为乳腺癌的治疗提供一种新的治疗策略。
Recent literature suggests that sEcad exerts pro-oncogenic effects, possibly acting as a ligand for the human epidermal growth factor family. Here we show that sEcad is a novel candidate protein for drug targeting since it is increased in human and mouse HER2-positive (HER2+) breast tumors, MMTV-PyMT bodily fluids and human cell culture systems. Mechanistically, we show that endogenous sEcad, and to a lesser extent membrane-bound E-cadherin, associates with HER1, HER2, and HER3 in human and MMTV-PyMT mouse HER2+ tumors and with HER1 in triple negative breast cancer (TNBC) specimens. Furthermore, addition of exogenous recombinant human E-cadherin/Fc chimeric protein (rhEcad/Fc; sEcad) to HER2+ MCF-7, SKBR3, and HER2-negative MDA-MB-231 TNBC cells, resulted in sEcad-HER receptor family interactions, activation of HER1–4 and downstream pro-survival signaling, including the MAPK-PI3K/Akt/mTOR pathways and IAP family members. Lastly, we demonstrate that sEcad exerts pro-oncogenic effects via HER signaling, and acts additively with the HER ligand EGF to promote HER2+ breast cancer proliferation and migration, as well as TNBC invasion. Because sEcad associates and activates many of the oncogenic pathways that tumors utilize for growth and survival and serum levels in patients correlates with clinical response, suggests that targeted therapy against sEcad in combination with other therapies may potentially offer a novel therapeutic strategy for the treatment of breast cancers.
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Survivin 是预后不良的乳腺癌患者短期生存的独立预测因子。
影响因子：
8.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.0500918102
发表时间：
2005-06-28
影响因子：
11.1
作者：
Maretzky, T;Reiss, K;Saftig, P
通讯作者：
Saftig, P
影响因子：
4.8
作者：
Najy, Abdo J.;Day, Kathleen C.;Day, Mark L.
通讯作者：
Day, Mark L.
影响因子：
8.8
作者：
Katayama, M.;Hirai, S.;Kamihagi, K.;Nakagawa, K.;Yasumoto, M.;Kato, I.
通讯作者：
Kato, I.
影响因子：
11.2
作者：
Asanuma, H;Torigoe, T;Sato, N
通讯作者：
Sato, N