Alteration of Trop-2 expression in breast cancer cells by clinically used therapeutic agents and acquired tamoxifen resistance,Breast Cancer

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Alteration of Trop-2 expression in breast cancer cells by clinically used therapeutic agents and acquired tamoxifen resistance
Breast Cancer ( IF 4.0 ) Pub Date : 2022-07-27 , DOI: 10.1007/s12282-022-01389-3
Jing Zhu _{1,

2} , Wenwen Wu ₁ , Yukiko Togashi ₁ , Naoe Taira Nihira ₁ , Yoshikazu Johmura _{3,

4} , Dajiang Zhu ₂ , Makoto Nakanishi ₄ , Yasuo Miyoshi ₅ , Tomohiko Ohta ₁

Affiliation

Background

Sacituzumab govitecan is an antibody–drug conjugate that delivers SN-38, an active metabolite of irinotecan, to the target molecule, trophoblast cell-surface antigen 2 (Trop-2). It is a promising drug for triple-negative breast cancer and is anticipated to be effective for luminal breast cancer. The efficacy of the agent relies on the expression of Trop-2 rather than its intracellular function. However, conditions that alter the Trop-2 expression have not been well investigated.

Methods

We tested a range of clinically related treatments for their effect on Trop-2 expression in cultured breast cancer cell lines.

Results

The expression level of Trop-2 differed among cell lines, independent of their subtypes, and was highly variable on treatment with kinase inhibitors, tamoxifen, irradiation, and chemotherapeutic agents including irinotecan. While inhibitors of AKT, RSK, and p38 MAPK suppressed the Trop-2 expression, tamoxifen treatment significantly increased Trop-2 expression in luminal cancer cell lines. Notably, luminal cancer cells with acquired resistance to tamoxifen also exhibited higher levels of Trop-2. We identified transcription factor EB (TFEB) as a possible mechanism underlying tamoxifen-induced elevation of Trop-2 expression. Tamoxifen triggers dephosphorylation of TFEB, an active form of TFEB, and the effect of tamoxifen on Trop-2 was prevented by depletion of TFEB. A luciferase reporter assay showed that Trop-2 induction by TFEB was dependent on a tandem E-box motif within the Trop-2 promoter region.

Conclusions

Overall, these results suggest that the effectiveness of sacituzumab govitecan could be altered by concomitant treatment and that tamoxifen could be a favorable agent for combined therapy.

中文翻译：

临床使用的治疗剂改变乳腺癌细胞中Trop-2的表达和获得性他莫昔芬耐药性

背景

Sacituzumab govitecan 是一种抗体-药物偶联物，可将 SN-38（伊立替康的一种活性代谢物）递送至靶分子滋养层细胞表面抗原 2 (Trop-2)。它是一种很有前景的治疗三阴性乳腺癌的药物，预计对管腔型乳腺癌有效。该药剂的功效依赖于 Trop-2 的表达，而不是其细胞内功能。然而，改变 Trop-2 表达的条件尚未得到很好的研究。

方法

我们测试了一系列临床相关治疗对培养的乳腺癌细胞系中 Trop-2 表达的影响。

结果

Trop-2 的表达水平在细胞系之间存在差异，与它们的亚型无关，并且在用激酶抑制剂、他莫昔芬、辐射和包括伊立替康在内的化学治疗剂治疗时变化很大。虽然 AKT、RSK 和 p38 MAPK 抑制剂抑制 Trop-2 表达，但他莫昔芬治疗显着增加了管腔癌细胞系中 Trop-2 的表达。值得注意的是，对他莫昔芬具有获得性耐药性的管腔癌细胞也表现出更高水平的 Trop-2。我们将转录因子 EB (TFEB) 确定为他莫昔芬诱导的 Trop-2 表达升高的可能机制。他莫昔芬触发 TFEB（TFEB 的一种活性形式）的去磷酸化，并且他莫昔芬对 Trop-2 的影响被 TFEB 的消耗所阻止。