Emerging Role of SOX Proteins in Breast Cancer Development and Maintenance

Abstract

The SOX genes encode a family of more than 20 transcription factors that are critical regulators of embryogenesis and developmental processes and, when aberrantly expressed, have been shown to contribute to tumor development and progression in both an oncogenic and tumor suppressive role. Increasing evidence demonstrates that the SOX proteins play essential roles in multiple cellular processes that mediate or contribute to oncogenic transformation and tumor progression. In the context of breast cancer, SOX proteins function both as oncogenes and tumor suppressors and have been shown to be associated with tumor stage and grade and poor prognosis. Experimental evidence demonstrates that a subset of SOX proteins regulate critical aspects of breast cancer biology including cancer stemness and multiple signaling pathways leading to altered cell proliferation, survival, and tumor development; EMT, cell migration and metastasis; as well as other tumor associated characteristics. This review will summarize the role of SOX family members as important mediators of tumorigenesis in breast cancer, with an emphasis on the triple negative or basal-like subtype of breast cancer, as well as examine the therapeutic potential of these genes and their downstream targets.

Keywords: Breast cancer; Cancer stem cells; EMT; Oncogene; Signaling; Sox.

Figure 1.. Groups and phylogenetic tree of human SOX proteins.

A rooted phylogenetic neighbor-joining tree for the human SOX full-length proteins was performed based on conserved amino acid sequences during evolution and divergence. To determine the robustness of the phylogeny relationship, 1000 bootstrap replicates were carried out. Each (%) bootstrap value is shown at the branch points.

Figure 2.. Analysis of SOX family member mRNA expression by breast cancer subtype.

Patterns of SOX gene expression were determined for 1,052 human breast tumors and 94 adjacent normal samples from the TCGA dataset; red indicates high mRNA expression and blue depicts low mRNA levels. Samples are organized by PAM50 molecular subtype: Basal-like (n=185), HER2 Enriched (HER2E; n=79), Luminal A (LumA; n=545), Luminal B (LumB; n=210) and Normal-like (n=33) tumors. SRY, SOX1, SOX3, SOX14, SOX20 and SOX21 were excluded from this analysis due to missing or insufficient data (expression values present in >80% of samples).

Figure 3.. Schematic overview of phenotypic functions rCegulated by SOX proteins in breast cancer.

The hallmarks of cancer regulated by SOX proteins in breast cancer are represented. The hallmarks that are specifically shown to be regulated by SOX proteins are highlighted in blue while those that have not been reported to be affected by SOX proteins are indicated in gray. Individual SOX proteins that have been reported to activate (red) or repress (blue) each of these hallmarks in the context of breast cancer are indicated.