γKlotho is a novel marker and cell survival factor in a subset of triple negative breast cancers.
γKlotho is a novel marker and cell survival factor in a subset of triple negative breast cancers.
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DOI：
10.18632/oncotarget.6006
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发表时间：
2016-01-19
期刊：
影响因子：
--
通讯作者：
Martinez ED
中科院分区：
文献类型：
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作者：
Trošt N;Peña-Llopis S;Koirala S;Stojan J;Potts PR;Fon Tacer K;Martinez ED
在过去十年中，乳腺癌死亡率有所下降。然而，三阴性乳腺癌（TNBC）仍然是一个具有挑战性的问题，主要是由于早期复发和缺乏分子驱动的治疗。迫切需要鉴定具有可被治疗靶向的共同分子特征的TNBC亚组。在这里，我们发现与Klotho和βKlotho相反，Klotho蛋白家族的第三个成员γKlotho在超过60%的TNBC中过表达，并且与较差的疾病进展相关。此外，我们发现γKlotho在促进细胞生长的TNBC细胞系亚群中表达。重要的是，我们证明了在这些细胞中，γKlotho是细胞存活所必需的，并且其缺失导致组成性ERK激活、细胞周期停滞和凋亡。有趣的是，我们观察到γ Klotho耗尽细胞中的氧化应激增加，表明γKlotho使癌细胞能够科普氧化环境，并且细胞变得依赖于其表达来维持这种生存优势。这些发现表明，γKlotho可能是患者的潜在标志物，这些患者将受益于改变氧化应激的治疗，并构成TN乳腺癌子集的新型药物靶点。
Over the last decade, breast cancer mortality has declined. However, triple negative breast cancer (TNBC) remains a challenging problem mostly due to early recurrence and lack of molecularly driven treatments. There is a critical need to identify subgroups of TNBC with common molecular features that can be therapeutically targeted. Here we show that in contrast to Klotho and βKlotho, the third member of the Klotho protein family, γKlotho, is overexpressed in more than 60% of TNBCs and correlates with poorer disease progression. Furthermore, we find that γKlotho is expressed in a subset of TNBC cell lines promoting cell growth. Importantly, we demonstrate that in these cells γKlotho is necessary for cell survival and that its depletion leads to constitutive ERK activation, cell cycle arrest and apoptosis. Interestingly, we observe increased oxidative stress in γKlotho-depleted cells suggesting that γKlotho enables cancer cells to cope with an oxidative environment and that cells become dependent on its expression to maintain this survival advantage. These findings indicate that γKlotho might be a potential marker for patients that would benefit from treatments that alter oxidative stress and constitutes a novel drug target for a subset of TN breast cancers.