PTK6 regulates growth and survival of endocrine therapy-resistant ER+ breast cancer cells
PTK6 regulates growth and survival of endocrine therapy-resistant ER+ breast cancer cells
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DOI：
10.1038/s41523-017-0047-1
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发表时间：
2017-11-17
影响因子：
5.9
通讯作者：
Irie, Hanna Y.
中科院分区：
文献类型：
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作者：
Ito, Koichi;Park, Sun Hee;Irie, Hanna Y.
非受体酪氨酸激酶PTK 6/BRK在多种肿瘤类型中高度表达，包括前列腺癌、卵巢癌和乳腺癌，并调节致癌表型，如增殖、迁移和存活。PTK 6抑制还克服了HER 2+乳腺癌的靶向治疗耐药性。尽管PTK 6在ER+管腔型乳腺癌中高度表达，但PTK 6在该亚型中的作用尚未阐明。在这项研究中，我们研究了PTK 6在ER+管腔乳腺癌细胞中的功能，包括那些对雌激素剥夺或用于治疗ER+癌症的靶向内分泌疗法相对耐药的细胞。PTK 6在ER+乳腺癌细胞中的增强表达增强了ER+乳腺癌细胞的生长，包括他莫昔芬处理的细胞。ER+乳腺癌细胞（包括对他莫昔芬、氟维司群和雌激素剥夺耐药的细胞）中PTK 6的下调可诱导细胞凋亡，如裂解PARP水平升高和AnnexinV+群体增加所证明。PTK 6下调损害了这些细胞在3D MatrigelTM培养物中的生长，并且实际上消除了他莫昔芬敏感性和抗性MCF-7异种移植物的原发性肿瘤生长。最后，我们发现p38 MAPK激活对于PTK 6下调诱导的细胞凋亡是至关重要的，这是我们先前报道的HER 2+乳腺癌细胞存活的机制，突出了PTK 6在乳腺癌亚型中的存活调节的保守机制。总之，我们的研究阐明了PTK 6在ER+管腔型乳腺癌中的关键功能，并支持PTK 6作为ER+乳腺癌的有吸引力的治疗靶点。
The non-receptor tyrosine kinase, PTK6/BRK, is highly expressed in multiple tumor types, including prostate, ovarian, and breast cancers, and regulates oncogenic phenotypes such as proliferation, migration, and survival. PTK6 inhibition also overcomes targeted therapy resistance of HER2+ breast cancer. Although PTK6 is highly expressed in ER+ Luminal breast cancers, the role of PTK6 in this subtype has not been elucidated. In this study, we investigated the functions of PTK6 in ER+ Luminal breast cancer cells, including those that are relatively resistant to estrogen deprivation or targeted endocrine therapies used in the treatment of ER+ cancers. Enhanced expression of PTK6 in ER+ breast cancer cells enhances growth of ER+ breast cancer cells, including tamoxifen-treated cells. Downregulation of PTK6 in ER+ breast cancer cells, including those resistant to tamoxifen, fulvestrant, and estrogen deprivation, induces apoptosis, as evidenced by increased levels of cleaved PARP, and an increase in the AnnexinV+ population. PTK6 downregulation impairs growth of these cells in 3D Matrigel (TM) cultures, and virtually abrogates primary tumor growth of both tamoxifen-sensitive and resistant MCF-7 xenografts. Finally, we show that p38 MAPK activation is critical for PTK6 downregulation-induced apoptosis, a mechanism that we previously reported for survival of HER2+ breast cancer cells, highlighting conserved mechanisms of survival regulation by PTK6 across breast cancer subtypes. In conclusion, our studies elucidate critical functions of PTK6 in ER+ Luminal breast cancers and support PTK6 as an attractive therapeutic target for ER+ breast cancers.