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同时激活 GLI1 和 Notch1 导致人类三阴性乳腺癌进展的种族差异。

Concomitant activation of GLI1 and Notch1 contributes to racial disparity of human triple negative breast cancer progression.

机构信息

Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States.

Department of Biology, MacMaster University, Hamilton, Canada.

出版信息

Elife. 2021 Dec 10;10:e70729. doi: 10.7554/eLife.70729.

DOI:10.7554/eLife.70729
PMID:34889737
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8664295/
Abstract

Mortality from triple negative breast cancer (TNBC) is significantly higher in African American (AA) women compared to White American (WA) women emphasizing ethnicity as a major risk factor; however, the molecular determinants that drive aggressive progression of AA-TNBC remain elusive. Here, we demonstrate for the first time that AA-TNBC cells are inherently aggressive, exhibiting elevated growth, migration, and cancer stem-like phenotype compared to WA-TNBC cells. Meta-analysis of RNA-sequencing data of multiple AA- and WA-TNBC cell lines shows enrichment of GLI1 and Notch1 pathways in AA-TNBC cells. Enrichment of GLI1 and Notch1 pathway genes was observed in AA-TNBC. In line with this observation, analysis of TCGA dataset reveals a positive correlation between GLI1 and Notch1 in AA-TNBC and a negative correlation in WA-TNBC. Increased nuclear localization and interaction between GLI1 and Notch1 is observed in AA-TNBC cells. Of importance, inhibition of GLI1 and Notch1 synergistically improves the efficacy of chemotherapy in AA-TNBC cells. Combined treatment of AA-TNBC-derived tumors with GANT61, DAPT, and doxorubicin/carboplatin results in significant tumor regression, and tumor-dissociated cells show mitigated migration, invasion, mammosphere formation, and CD44/CD24 population. Indeed, secondary tumors derived from triple-therapy-treated AA-TNBC tumors show diminished stem-like phenotype. Finally, we show that TNBC tumors from AA women express significantly higher level of GLI1 and Notch1 expression in comparison to TNBC tumors from WA women. This work sheds light on the racial disparity in TNBC, implicates the GLI1 and Notch1 axis as its functional mediators, and proposes a triple-combination therapy that can prove beneficial for AA-TNBC.

摘要

三阴性乳腺癌（TNBC）患者的死亡率在非裔美国女性（AA）中明显高于白种裔美国女性（WA），强调了种族是一个主要的危险因素；然而，导致 AA-TNBC 侵袭性进展的分子决定因素仍难以捉摸。在这里，我们首次证明 AA-TNBC 细胞具有内在的侵袭性，与 WA-TNBC 细胞相比，其表现出更高的生长、迁移和癌症干细胞样表型。对多个 AA 和 WA-TNBC 细胞系的 RNA-seq 数据进行的荟萃分析表明，AA-TNBC 细胞中 GLI1 和 Notch1 途径富集。在 AA-TNBC 中观察到 GLI1 和 Notch1 途径基因的富集。与这一观察结果一致，对 TCGA 数据集的分析表明，AA-TNBC 中 GLI1 和 Notch1 呈正相关，而 WA-TNBC 中呈负相关。在 AA-TNBC 细胞中观察到 GLI1 和 Notch1 的核定位增加和相互作用。重要的是，抑制 GLI1 和 Notch1 协同提高了 AA-TNBC 细胞化疗的疗效。用 GANT61、DAPT 和多柔比星/卡铂联合治疗 AA-TNBC 衍生的肿瘤导致显著的肿瘤消退，并且肿瘤相关细胞显示出迁移、侵袭、类器官形成和 CD44/CD24 群体的减轻。事实上，来自三重治疗处理的 AA-TNBC 肿瘤的次级肿瘤显示出减弱的干细胞样表型。最后，我们表明，与 WA 女性的 TNBC 肿瘤相比，AA 女性的 TNBC 肿瘤表达显著更高水平的 GLI1 和 Notch1。这项工作揭示了 TNBC 中的种族差异，暗示了 GLI1 和 Notch1 轴作为其功能介质，并提出了一种三重联合治疗方法，可能对 AA-TNBC 有益。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/fa42fd86de0f/elife-70729-fig7-figsupp2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/884c1407d1a8/elife-70729-fig6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/bb86d978768a/elife-70729-fig7-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/fa42fd86de0f/elife-70729-fig7-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/ffac82049f12/elife-70729-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/e362e981cc1e/elife-70729-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/2ad14e804543/elife-70729-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/6f855d0986d9/elife-70729-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/5ec09ffd27f5/elife-70729-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/bee057b8a108/elife-70729-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/7f0e45c169b5/elife-70729-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/cdd9cab67f08/elife-70729-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/2233e36734d6/elife-70729-fig5-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/884c1407d1a8/elife-70729-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/28a3dc1a0b20/elife-70729-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/ba4dee625248/elife-70729-fig6-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/31a1e47103ca/elife-70729-fig6-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/7559d3aae481/elife-70729-fig6-figsupp4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/9fd568648755/elife-70729-fig6-figsupp5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/fbd5e292cebb/elife-70729-fig6-figsupp6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/64db62e9b354/elife-70729-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/bb86d978768a/elife-70729-fig7-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/8664295/fa42fd86de0f/elife-70729-fig7-figsupp2.jpg

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