先前的研究指出，超氧化物歧化酶[Cu-Zn]（SOD1）的過度表達與乳腺癌患者的較差預後有相關。因此，SOD1被認為是治療乳腺癌的潛在標靶分子。四硫代鉬酸膽鹼（ATN-224）是臨床上用於治療威爾遜氏病的銅螯合劑。 ATN-224通過抑制SOD1活性誘導癌細胞死亡，SOD1是一個重要的抗氧化酶。儘管ATN-224目前正在癌症患者中進行臨床試驗，其抗癌的分子作用機制尚不清楚，目前認為ATN-224會藉由抑制血管新生以抑制腫瘤生長。但是ATN-224是否可用於治療不同乳腺癌亞型尚不清楚，在我們研究中，我們評估了ATN-224在不同乳腺癌亞型中的抗癌效果和其作用機制。
在本篇的研究中，我們通過分析線上的臨床數據發現，SOD1的高表現量與乳腺癌患者較差的總體生存率和無復發生存率相關。有趣的是，MTT細胞存活率測定的結果表明在三陰性亞型的MDA-MB-231與MDA-MB-453（三陰性亞型）細胞中表現出最佳的效力在本篇所使用的四種乳腺癌細胞中（即MDA-MB-231，MDA-MB-453，MCF-7（管狀A型），SK-BR-3（富含HER2亞型）。令人驚訝的是，儘管ATN-224抑制了MDA-MB-231和MCF-7細胞中SOD1的活性，但它僅增加了MDA-MB-231細胞中的細胞ROS水平。為了研究ATN-224在MDA-MB-231細胞中的作用分子機制，我們進行轉錄組的分析（mRNAseq）。對鑑定出的差異表達基因（DEGs）進行KEGG和GO分析和西方墨點法分析，結果發現ATN-224激活p38-p53-p21信號傳導途徑，並誘導MDA-MB-231和MCF-7細胞衰老（Cellular senescence）。 ATN-224還下調抗凋亡分子和促癌基因存活素(Survivin)的表達，並誘導乳腺癌細胞的凋亡。令人驚訝地是ATN-224上調雌激素受體陽性（ER+）MCF-7細胞中磷酸化HER2的表達，但是下調雌激素受體陰性MDA-MB-231細胞中磷酸化HER2的表達。此外，需要更高濃度的ATN-224來抑制MCF-7細胞中SOD1的總細胞活性，已知它與MDA-MB-231細胞相比具有更高的SOD1活性。
此篇的研究結論是我們證明了ATN-224在不同的乳腺癌細胞中表現出不同的抗癌效果和分子作用機制。本研究的發現表明，ATN-224可能更有效地用於治療三陰性乳腺癌。了解ATN-224在不同乳腺癌細胞中的不同分子作用機制可為將來選擇最適合乳腺癌組合治療藥物提供重要信息。

Previous studies revealed that overexpression of SOD1 is positively correlated with poorer prognosis in breast cancer patients. Therefore, SOD1 was suggested as a potential target for breast cancer treatment. Tetrathiomolybdate (ATN-224) is a copper chelator clinically used for the treatment of Wilson's Disease. ATN-224 can induce cancer cell death through targeting Superoxide dismutase [Cu-Zn] (SOD1), which is an important anti-oxidant enzyme. Despite ATN-224 is currently undergoing clinical trials in cancer patients; its effects and the molecular mechanism of action on cancer cells are still unclear, as the tumor targeting effect of ATN-224 is believed to be related to its anti-angiogenic property. It is also unclear on whether ATN-224 is of potential on treating a specific breast cancer subtype. In this study, we evaluated the potency and investigated the mechanism of action of ATN-224 in different breast cancer subtypes.

In the current study, we found that high expression level of SOD1 is correlated with poorer overall survival and recurrence-free survival in breast cancer patients by analyzing the clinical data available online. Interestingly, results of the MTT cell viability assay revealed that ATN-224 exhibits the highest potency in MDA-MB-231 and MDA-MB-453 (triple-negative subtype) among the four examined breast cancer cell lines [i.e. MDA-MB-231,MDA-MB-453 MCF-7 (luminal A subtype), SK-BR-3 (HER2-enriched subtype)]. Surprisingly, despite ATN-224 inhibited the activity of SOD1 in both MDA-MB-231 and MCF-7 cells, it only increased the cellular ROS level in MDA-MB-231 cells. Transcriptomic analysis (mRNAseq) was carried out to investigate the molecular mechanism of action of ATN-224 in MDA-MB-231 cells. KEGG enrichment pathway and GO enrichment analysis on the identified differentially expressed genes (DEGs) and Western blot analysis revealed that ATN-224 activated the p38-p53-p21 signaling pathway and induces cellular senescence in MDA-MB-231 and MCF-7 cells. ATN-224 also downregulated the expression of survivin, which is a well-known anti-apoptotic molecule and a proto-oncogene, and induced apoptosis in breast cancer cells. Surprisingly, ATN-224 upregulated the expression level of phospho-HER2 in the estrogen receptor positive (ER+) MCF-7 cells but downregulated the expression of phospho-HER2 in the ER- MDA-MB-231 cells. Moreover, higher concentration of ATN-224 was required to inhibit the total cellular activity of SOD1 in MCF-7 cells, which is known to exhibit higher SOD1 activity as compared to MDA-MB-231 cells.

In conclusion, we demonstrated that ATN-224 exhibits differential potency and molecular mechanism of actions in different breast cancer cells. Findings of the current study suggest that ATN-224 may be more effective for use in treating triple-negative breast cancer. Understanding the differential molecular mechanism of action of ATN-224 in different breast cancer cells may provide important information for selecting the most suitable drug for breast cancer combinational therapy in the future.

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