Genome-wide association studies have identified a breast cancer risk locus at 19q13.31. The candidate causal variants at this locus are located in the first exon of KCNN4. KCNN4, which regulates membrane potential and Ca2+ signaling, is a good candidate for drug repositioning because its inhibitor, Senicapoc, has been shown to be well tolerated in Phase-II and -III clinical trials for asthma and sickle cell anemia.
To understand the role of KCNN4 in breast cancer we evaluated public mRNA expression data to determine whether the allele at 19q13.31 associated with increased breast cancer risk was associated with KCNN4 expression. We also used immunohistochemistry to evaluate the relationship between KCNN4 protein expression and breast cancer survival. We then used the inhibitor, Senicapoc in numerous preclinical mouse models of breast cancer to determine if it would delay tumor development.
Analysis of the Genotype-Tissue Expression Project showed that the allele at 19q13.31 associated with increased breast cancer risk is associated with increased KCNN4 expression, suggesting that inhibiting KCNN4 might reduce breast cancer risk. High KCNN4 expression was found in triple negative and basal breast cancers, and in chemoresistant breast cancers. Our preclinical prevention models showed that Senicapoc could delay the development of mammary tumors in two murine models (DMBA induced tumours and SSM1 syngeneic tumours) but not in our MMTV BRCA1 model. As a therapy, it slowed the growth of syngeneic (4T1) triple negative breast cancers and improved the response to chemotherapy when used in combination. This was also seen in the MMTV BRCA1 mouse model. The mode of action is postulated to be via macrophages as we see changes in their numbers, polarization and function as determined by scRNAseq, flow cytometric analysis and functional ex-vivo analysis.
These results provide a rationale for clinical testing of Senicapoc (and other macrophage modulators) for treating triple negative breast cancers.