Wang Ming-Yang, Huang Hsin-Yi, Kuo Yao-Lung, Lo Chiao, Sun Hung-Yu, Lyu Yu-Jhen, Chen Bo-Rong, Li Jie-Ning, Chen Pai-Sheng
Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan.
Department of Pathology, National Taiwan University Hospital, Taipei 100, Taiwan.
Cancers (Basel). 2019 Feb 12;11(2):210. doi: 10.3390/cancers11020210.
Tamoxifen is the most widely used hormone therapy in estrogen receptor-positive (ER+) breast cancer, which accounts for approximately 70% of all breast cancers. Although patients who receive tamoxifen therapy benefit with respect to an improved overall prognosis, resistance and cancer recurrence still occur and remain important clinical challenges. A recent study identified TAR (HIV-1) RNA binding protein 2 (TARBP2) as an oncogene that promotes breast cancer metastasis. In this study, we showed that TARBP2 is overexpressed in hormone therapy-resistant cells and breast cancer tissues, where it enhances tamoxifen resistance. Tamoxifen-induced TARBP2 expression results in the desensitization of ER+ breast cancer cells. Mechanistically, tamoxifen post-transcriptionally stabilizes TARBP2 protein through the downregulation of Merlin, a TARBP2-interacting protein known to enhance its proteasomal degradation. Tamoxifen-induced TARBP2 further stabilizes SOX2 protein to enhance desensitization of breast cancer cells to tamoxifen, while similar to TARBP2, its induction in cancer cells was also observed in metastatic tumor cells. Our results indicate that the TARBP2-SOX2 pathway is upregulated by tamoxifen-mediated Merlin downregulation, which subsequently induces tamoxifen resistance in ER+ breast cancer.
他莫昔芬是雌激素受体阳性（ER+）乳腺癌中使用最广泛的激素疗法，ER+乳腺癌约占所有乳腺癌的70%。尽管接受他莫昔芬治疗的患者在改善总体预后方面有所获益，但耐药性和癌症复发仍然存在，并且仍然是重要的临床挑战。最近一项研究确定HIV-1反式激活应答RNA结合蛋白2（TARBP2）是一种促进乳腺癌转移的癌基因。在本研究中，我们发现TARBP2在激素治疗耐药细胞和乳腺癌组织中过表达，在这些组织中它增强了他莫昔芬耐药性。他莫昔芬诱导的TARBP2表达导致ER+乳腺癌细胞脱敏。从机制上讲，他莫昔芬通过下调Merlin来转录后稳定TARBP2蛋白，Merlin是一种已知可增强TARBP2蛋白酶体降解的与TARBP2相互作用的蛋白。他莫昔芬诱导的TARBP2进一步稳定SOX2蛋白，以增强乳腺癌细胞对他莫昔芬的脱敏作用，并且与TARBP2类似，在转移瘤细胞中也观察到其在癌细胞中的诱导。我们的结果表明，TARBP2-SOX2通路通过他莫昔芬介导的Merlin下调而上调，随后在ER+乳腺癌中诱导他莫昔芬耐药。
