Kaiso modulates androgen receptor expression in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that presents therapeutic challenges due to the lack of expression of biomarkers required for conventional targeted treatments. Although a subset of TNBC tumors respond to androgen receptor (AR) inhibitors, the majority exhibit low AR expression and poor outcomes. These AR-negative tumors have been subclassified as quadruple-negative breast cancer (QNBC). Notably, women of African ancestry (WAA) experience a disproportionate burden of TNBC and higher mortality compared to white women, a disparity not fully explained by socio-economic factors, thus suggesting a genetic susceptibility. The transcription factor Kaiso, previously implicated in TNBC progression and poor survival in WAA patients, may play a key role in QNBC biology.

Expression profiling of TNBC tumors from WAA and white women was performed using publicly available datasets and tissue microarrays. To examine the role of Kaiso in AR regulation, we generated CRISPR-Cas9 Kaiso knockout TNBC cell lines and assessed AR expression using chromatin immunoprecipitation, immunoblotting, RT-qPCR and promoter-reporter assays. Cell viability, migration and invasion assays were used to evaluate the effect of Kaiso knockout on sensitivity to the AR inhibitor enzalutamide.

High Kaiso expression combined with low AR expression correlated with poorer survival across breast cancer subtypes, including TNBC. WAA expressed significantly lower AR expression and a higher prevalence of the QNBC subtype. Kaiso associated with the endogenous AR promoter, and Kaiso knockout in TNBC cells increased AR expression while reducing ACSL4, an AR target gene that promotes metastasis through phospholipid remodeling. Notably, Kaiso knockout cells were more sensitive to enzalutamide compared to parental cells and reduced migration and invasion.

Collectively, our findings implicate Kaiso as a key player in TNBC and QNBC, highlighting its potential as a druggable target for improving outcomes in these aggressive breast cancer subtypes.