The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer.
The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer.
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DOI：
10.18632/oncotarget.13579
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发表时间：
2017-01-10
期刊：
影响因子：
--
通讯作者：
Pandey A
中科院分区：
文献类型：
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作者：
Wu X;Zahari MS;Renuse S;Kelkar DS;Barbhuiya MA;Rojas PL;Stearns V;Gabrielson E;Malla P;Sukumar S;Mahajan NP;Pandey A
乳腺癌是全世界女性中最常见的癌症。约15-20%的乳腺癌不表达雌激素受体、孕激素受体或HER2受体，因此被统称为三阴性乳腺癌（TNBC）。与其他类型的乳腺癌相比，这些肿瘤通常具有相对的侵袭性，而且由于缺乏有效的靶向治疗，这一问题更加复杂。在我们之前的磷蛋白组学分析工作中，我们发现非受体酪氨酸激酶TNK2在大多数侵袭性TNBC细胞系中被激活。在目前的研究中，我们发现TNK2在乳腺癌细胞系中的高表达与高增殖、侵袭和集落形成能力相关。我们证明，敲低TNK2表达可以显著抑制体外TNBC细胞的侵袭性和增殖优势，以及异种移植小鼠模型中的肿瘤形成。此外，用小分子抑制剂(R)-9bMS抑制TNK2可显著降低TNBC的增殖。最后，我们发现高级别基底样乳腺癌中TNK2的高水平表达与较差的患者预后显著相关。综上所述，我们的研究表明，TNK2是治疗TNBC的一个新的潜在治疗靶点。
Breast cancer is the most prevalent cancer in women worldwide. About 15-20% of all breast cancers do not express estrogen receptor, progesterone receptor or HER2 receptor and hence are collectively classified as triple negative breast cancer (TNBC). These tumors are often relatively aggressive when compared to other types of breast cancer, and this issue is compounded by the lack of effective targeted therapy. In our previous phosphoproteomic profiling effort, we identified the non-receptor tyrosine kinase TNK2 as activated in a majority of aggressive TNBC cell lines. In the current study, we show that high expression of TNK2 in breast cancer cell lines correlates with high proliferation, invasion and colony forming ability. We demonstrate that knockdown of TNK2 expression can substantially suppress the invasiveness and proliferation advantage of TNBC cells in vitro and tumor formation in xenograft mouse models. Moreover, inhibition of TNK2 with small molecule inhibitor (R)-9bMS significantly compromised TNBC proliferation. Finally, we find that high levels of TNK2 expression in high-grade basal-like breast cancers correlates significantly with poorer patient outcome. Taken together, our study suggests that TNK2 is a novel potential therapeutic target for the treatment of TNBC.