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

Sumit Siddharth,Sheetal Parida,Chenguang Wang,Balazs Gyorffy,Shawn Hercules,David Lim,Nethaji Muniraj,Arumugam Nagalingam,Dipali Sharma,Juliet M Daniel

doi:10.7554/elife.70729

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.

Highlights

While breast cancer remains the most common cancer among women worldwide, mortality associated with breast cancer has been declining owing to the development of novel therapeutics and ensuing advances in clinical care
Our study revealed an enrichment of glioma-associated oncogene homolog 1 (GLI1) and Notch1 pathways in AA-triple negative breast cancer (TNBC) as the key node and we found a positive correlation between GLI1 and Notch1 in AA-T NBC tumors in contrast to White American (WA)-T NBC tumors
With an aim to investigate the racial disparity in TNBC, we started this investigation by analyzing the SEER (The Surveillance, Epidemiology, and End Results Program) data focusing on differences between AA and WA women

Summary

Introduction

While breast cancer remains the most common cancer among women worldwide, mortality associated with breast cancer has been declining owing to the development of novel therapeutics and ensuing advances in clinical care. Despite lower incidence rates (126.7/100,000 for AA vs 130.8/100,000 for WA), AA women are 42% more likely to succumb to breast cancer-related mortality (DeSantis et al, 2019; Siegel et al, 2020). Do AA women have higher TNBC incidence, but the survival rate for TNBC is significantly lower in AA women in comparison to WA women (5-y ear relative survival of only 14% for AA in comparison to 36% for WA) Factors such as increased prevalence of obesity and comorbidities; late stage at diagnosis; aggressive tumor characteristics; and reduced access to timely prevention, early detection, and high-q uality treatment may contribute to higher TNBC-related mortality in AA women. It is important to note that this disparity in TNBC-r elated survival in AA women vs. WA women is evident even after adjusting for socioeconomic status and access to medical care, strongly indicating a biological basis (Carey et al, 2006; Dietze et al, 2015)

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Discussion

Conclusion