Differential roles of SALL transcription factors in breast cancer: Potential biomarkers.

[BACKGROUND] Aberrant alterations in transcription factors often disrupt key signalling pathways, contributing to oncogenesis in multiple cancers, including breast cancer. Spalt-like (SALL) transcription factors are a highly conserved family of proteins with distinctive zinc finger motifs that are emerging as crucial players in tumorigenesis. Despite their pivotal roles in oncogenesis, limited studies have been carried out to explore their roles specifically in breast cancer.

[METHODS] We profiled the SALL genes using omics databases and bioinformatic tools including cBioPortal, UALCAN, GeneMANIA, Human Protein Atlas (HPA), Kaplan-Meier plotter, STRING analysis, TIMER 3.0, along with connected miRNAs and transcription factors through miRNet database. We also evaluated these genes in in vitro and clinical samples for mRNA, protein expression, and localization.

[RESULTS] Our analysis revealed several crucial key predictive molecular signatures, in which differential mRNA, protein, and methylation, as well as survival status, were found. Validation of the results demonstrated distinct differential expression patterns of SALL transcription factors across breast cancer subtypes. In comparison to adjacent normal tissues, SALL1 and SALL2 exhibited significantly lower expression in aggressive subtypes (TNBC), whereas SALL3 showed significantly higher expression only in luminal breast cancer, and SALL4 showed higher expression in all luminal, HER2, and triple negative breast cancer, which suggests the dual nature of SALL transcription factors in breast cancer. Moreover, we observed that SALL genes are significantly associated with survival, SALL2 (HR = 0.68, (0.53-0.85) P = 9e-04 for overall survival; HR = 0.68, (0.62-0.75) P = 7.4e-14 in Relapse-Free Survival), SALL3 (HR = 1.39 (1.05-1.08), P = 0.021; HR = 0.68 (0.58-0.8), P = 1.1e-06) and SALL4 (HR = 1.69 (1.29-2.22), P = 1.2e-04) (HR = 0.72 (0.61-0.83), P = 1.4e-05) are associated with survival.

[CONCLUSION] This work underscores the potential of the SALL transcription factor members as novel biomarkers and therapeutic targets and may contribute to the development of transcription-based interventions for breast cancer management.