Investigating Kaiso and TGFβ signaling crosstalk in epithelial-to-mesenchymal transition in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is the most difficult-to-treat breast cancer (BCa) subtype due to its aggressive, highly metastatic nature, and lack of targeted therapies. Increasing evidence implicates the transcription factor Kaiso in TNBC’s increased metastatic potential. In mouse xenograft models, Kaiso-depleted TNBC cells formed little to no metastatic lesions in the lungs or liver compared to parental Kaiso-expressing TNBC cells. Furthermore, increased nuclear Kaiso localization correlates with tumors of a higher histological grade and poorer survival. Kaiso has been implicated in metastasis by promoting epithelial-to-mesenchymal transition (EMT), a cellular program that is characterized by the loss of cell-to-cell adhesion and the adoption of mesenchymal properties that promote migration and invasion. While characterizing the mechanisms behind Kaiso’s role in EMT, we determined that Kaiso regulates the expression of various proteins in the Transforming Growth Factor Beta (TGFβ) signaling pathway, another potent inducer of EMT that also participates in BCa progression. Interestingly, we also observed that TGFβ1 treatment increases Kaiso expression in our TNBC cell lines. Chromatin immunoprecipitation (ChIP)-PCR analysis of the Kaiso promoter revealed that the TGFβ transcription factors SMAD2/3 bind to the Kaiso promoter directly, indicating that in addition to regulating TGFβ signaling proteins, Kaiso is also a downstream target of TGFβ. To further examine Kaiso's role in TNBC aggressiveness and metastasis, we will fully characterize this Kaiso-TGFβ feedback loop and examine Kaiso and TGFβ expression in TNBC tissues to determine if there is a unique Kaiso/TGF-β signature that could be used as diagnostic/prognostic biomarkers for TNBC.