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Concomitant activation of GLI1 and Notch1 contributes to racial disparity of human triple negative breast cancer progression.
| Content Provider | Europe PMC |
|---|---|
| Author | Siddharth, Sumit Parida, Sheetal Muniraj, Nethaji Hercules, Shawn Lim, David Nagalingam, Arumugam Wang, Chenguang Gyorffy, Balazs Daniel, Juliet M Sharma, Dipali |
| Editor | Golemis, Erica A Akhmanova, Anna |
| Copyright Year | 2021 |
| 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. |
| Journal | eLife |
| Volume Number | 10 |
| PubMed Central reference number | PMC8664295 |
| PubMed reference number | 34889737 |
| e-ISSN | 2050084X |
| DOI | 10.7554/elife.70729 |
| Language | English |
| Publisher | eLife Sciences Publications, Ltd |
| Publisher Date | 2021-12-10 |
| Access Restriction | Open |
| Rights License | This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. © 2021, Siddharth et al |
| Subject Keyword | racial disparity GLI1 Notch1 African American women White American women triple negative breast cancer Human Mouse |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Microbiology Neuroscience Medicine Biochemistry, Genetics and Molecular Biology |
