Huang Yu-Hsiang, Chu Pei-Yi, Chen Ji-Lin, Huang Chun-Teng, Lee Chia-Han, Lau Ka-Yi, Wang Wan-Lun, Wang Yu-Ling, Lien Pei-Ju, Tseng Ling-Ming, Liu Chun-Yu
School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
Department of Pathology, Show Chwan Memorial Hospital, Changhua City 50091, Taiwan.
J Clin Med. 2018 Aug 28;7(9):245. doi: 10.3390/jcm7090245.
Adjuvant tamoxifen reduces the recurrence rate of estrogen receptor (ER)-positive breast cancer. Previous in vitro studies have suggested that tamoxifen can affect the cancerous inhibitor of protein phosphatase 2A (CIP2A)/protein phosphatase 2A (PP2A)/phosphorylation Akt (pAkt) signaling in ER-negative breast cancer cells. In addition to CIP2A, SET nuclear proto-oncogene (SET) oncoprotein is another intrinsic inhibitor of PP2A, participating in cancer progression. In the current study, we explored the clinical significance of SET, CIP2A, PP2A, and Akt in patients with ER-positive breast cancer receiving adjuvant tamoxifen. A total of 218 primary breast cancer patients receiving adjuvant tamoxifen with a median follow-up of 106 months were analyzed, of which 17 (7.8%) experienced recurrence or metastasis. In an immunohistochemical (IHC) stain, SET overexpression was independently associated with worse recurrence-free survival (RFS) (hazard ratio = 3.72, 95% confidence interval 1.26⁻10.94, = 0.017). In silico analysis revealed mRNA expressions of , , and significantly correlated with worse RFS. In vitro, SET overexpression reduced tamoxifen-induced antitumor effects and drove luciferase activity in an Estrogen receptor element (ERE)-dependent manner. In conclusion, SET is a prognostic biomarker in patients with primary ER-positive breast cancer receiving adjuvant tamoxifen and may contribute to the failure of the tamoxifen treatment by modulating the ER signaling. Our study warrants further investigation into the potential role of SET in ER-positive breast cancer.
辅助性他莫昔芬可降低雌激素受体（ER）阳性乳腺癌的复发率。以往的体外研究表明，他莫昔芬可影响ER阴性乳腺癌细胞中蛋白磷酸酶2A的癌性抑制剂（CIP2A）/蛋白磷酸酶2A（PP2A）/磷酸化Akt（pAkt）信号通路。除CIP2A外，SET核原癌基因（SET）癌蛋白是PP2A的另一种内在抑制剂，参与癌症进展。在本研究中，我们探讨了SET、CIP2A、PP2A和Akt在接受辅助性他莫昔芬治疗的ER阳性乳腺癌患者中的临床意义。对218例接受辅助性他莫昔芬治疗且中位随访106个月的原发性乳腺癌患者进行了分析，其中17例（7.8%）出现复发或转移。在免疫组织化学（IHC）染色中，SET过表达与无复发生存期（RFS）较差独立相关（风险比=3.72，95%置信区间1.26⁻10.94， = 0.017）。计算机分析显示， 、 和 的mRNA表达与较差的RFS显著相关。在体外，SET过表达降低了他莫昔芬诱导的抗肿瘤作用，并以雌激素受体元件（ERE）依赖的方式驱动荧光素酶活性。总之，SET是接受辅助性他莫昔芬治疗的原发性ER阳性乳腺癌患者的预后生物标志物，可能通过调节ER信号通路导致他莫昔芬治疗失败。我们的研究值得进一步探讨SET在ER阳性乳腺癌中的潜在作用。
