Department of Pathology and Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
Sci Rep. 2023 Sep 22;13(1):15843. doi: 10.1038/s41598-023-43121-x.
Proteasomes are multi-subunit complexes that specialize in protein degradation. Cancer cells exhibit a heightened dependence on proteasome activity, presumably to support their enhanced proliferation and other cancer-related characteristics. Here, a systematic analysis of TCGA breast cancer datasets revealed that proteasome subunit transcript levels are elevated in all intrinsic subtypes (luminal, HER2-enriched, and basal-like/triple-negative) when compared to normal breast tissue. Although these observations suggest a pan-breast cancer utility for proteasome inhibitors, our further experiments with breast cancer cell lines and patient-derived xenografts (PDX) pointed to triple-negative breast cancer (TNBC) as the most sensitive subtype to proteasome inhibition. Finally, using TNBC cells, we extended our studies to in vivo xenograft experiments. Our previous work has firmly established a cytoprotective role for the transcription factor NRF1 via its ability to upregulate proteasome genes in response to proteasome inhibition. In further support of this notion, we show here that NRF1 depletion significantly reduced tumor burden in an MDA-MB-231 TNBC xenograft mouse model treated with carfilzomib. Taken together, our results point to TNBC as a particularly vulnerable breast cancer subtype to proteasome inhibition and provide a proof-of-principle for targeting NRF1 as a viable means to increase the efficacy of proteasome inhibitors in TNBC tumors.
蛋白酶体是专门降解蛋白质的多亚基复合物。癌细胞对蛋白酶体活性的依赖性增强，可能是为了支持其增强的增殖和其他与癌症相关的特征。在这里，对 TCGA 乳腺癌数据集的系统分析表明，与正常乳腺组织相比，所有内在亚型（luminal、HER2 富集型和基底样/三阴性）的蛋白酶体亚基转录水平都升高。尽管这些观察结果表明蛋白酶体抑制剂对泛乳腺癌具有应用价值，但我们对乳腺癌细胞系和患者来源异种移植（PDX）的进一步实验表明，三阴性乳腺癌（TNBC）对蛋白酶体抑制最敏感。最后，使用 TNBC 细胞，我们将研究扩展到体内异种移植实验。我们之前的工作通过其在蛋白酶体抑制后上调蛋白酶体基因的能力，牢固地确立了转录因子 NRF1 的细胞保护作用。进一步支持这一观点，我们在这里表明，在接受卡非佐米治疗的 MDA-MB-231 TNBC 异种移植小鼠模型中，NRF1 耗竭显著降低了肿瘤负担。总之，我们的结果表明 TNBC 是对蛋白酶体抑制特别脆弱的乳腺癌亚型，并为靶向 NRF1 作为增加 TNBC 肿瘤中蛋白酶体抑制剂疗效的可行方法提供了原理验证。
