Mislocalization of p27 to the cytoplasm of breast cancer cells confers resistance to anti-HER2 targeted therapy.
Mislocalization of p27 to the cytoplasm of breast cancer cells confers resistance to anti-HER2 targeted therapy.
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DOI：
10.18632/oncotarget.2871
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发表时间：
2014-12-30
期刊：
影响因子：
--
通讯作者：
Roberts JM
中科院分区：
文献类型：
--
作者：
Zhao H;Faltermeier CM;Mendelsohn L;Porter PL;Clurman BE;Roberts JM
作为一种细胞周期抑制剂和肿瘤抑制剂，p27在人类癌症中经常被错误调节。降解增加是最常见的失调机制，然而在一些癌症中，p27从其细胞周期抑制位置错误定位在细胞核中，到细胞质中。在正常细胞中，胞质p27具有不同于其细胞周期调节核功能的功能。因此，一个重要的问题是，在肿瘤细胞中，p27定位于细胞质是否主要是取消其对细胞增殖的抑制作用的机制，或者胞质p27是否具有更直接的致癌作用。为了研究p27在人类癌症中的错误定位，我们筛选了一组常见的乳腺癌细胞系。我们观察到p27仅在Her 2+细胞系中积累在细胞质中。为了解决在Her 2+乳腺癌细胞中p27错误定位的意义，我们询问了对双重Her 2/EGFR激酶抑制剂拉帕替尼的细胞反应。使用shRNA敲低p27使Her 2+细胞对拉帕替尼诱导的凋亡敏感。此外，组成型细胞质形式的p27（p27ΔNLS）的表达逆转了拉帕替尼诱导的细胞凋亡，表明细胞质p27通过抑制细胞凋亡导致Her 2+乳腺癌细胞中拉帕替尼耐药。我们的研究结果表明，p27定位可能是有用的Her 2+乳腺癌患者的治疗反应的预测生物标志物。
As a cell cycle inhibitor and tumor suppressor, p27 is frequently misregulated in human cancers. Increased degradation is the most common mechanism of misregulation, however in some cancers, p27 is mislocalized from its cell cycle inhibitory location in the nucleus, to the cytoplasm. In normal cells cytoplasmic p27 has functions that are distinct from its cell cycle-regulatory nuclear functions. Therefore, an important question is whether localization of p27 to the cytoplasm in tumor cells is primarily a mechanism for cancelling its inhibitory effect on cell proliferation, or whether cytoplasmic p27 has more direct oncogenic actions. To study p27 mislocalization in human cancers we screened a panel of common breast cancer cell lines. We observed that p27 accumulated in the cytoplasm exclusively in cell lines that are Her2+. To address the significance of p27 mislocalization in Her2+ breast cancer cells we interrogated the cellular response to the dual-Her2/EGFR kinase inhibitor, lapatinib. Knockdown of p27 using shRNA sensitized Her2+ cells to lapatinib-induced apoptosis. Moreover, expression of a constitutively cytoplasmic form of p27 (p27ΔNLS) reversed the lapatinib-induced apoptosis, suggesting that cytoplasmic p27 contributed to lapatinib resistance in Her2+ breast cancer cells by suppressing apoptosis. Our results suggest that p27 localization may be useful as a predictive biomarker of therapeutic response in patients with Her2+ breast cancers.
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DOI：
10.1158/1078-0432.ccr-08-0170
发表时间：
2009-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kim J;Jonasch E;Alexander A;Short JD;Cai S;Wen S;Tsavachidou D;Tamboli P;Czerniak BA;Do KA;Wu KJ;Marlow LA;Wood CG;Copland JA;Walker CL
通讯作者：
Walker CL
影响因子：
9.8
作者：
Coller HA;Sang L;Roberts JM
通讯作者：
Roberts JM
影响因子：
8
作者：
Serres, M. P.;Zlotek-Zlotkiewicz, E.;Besson, A.
通讯作者：
Besson, A.
DOI：
10.1097/pgp.0b013e3181b64ec3
发表时间：
2010-01-01
影响因子：
2.4
作者：
Duncan, Timothy J.;Al-Attar, Ahmad;Durrant, Lindy G.
通讯作者：
Durrant, Lindy G.
影响因子：
16
作者：
Levkau, B;Koyama, H;Ross, R
通讯作者：
Ross, R