| Autor: |
Christos Xiao, Mariska Miranda, Wei Shi, Jonathan Beesley, Jodi M. Saunus, Andrew Civitarese, Debra M. Black, Meagan Ruppert, Melrine Pereira, Susan Jackson, Zachary Teale, Dylan Carter-Cusack, Lauren Kalinowski, Jamie R. Kutasovic, Amy E. McCart Reed, Herlina Y. Handoko, XiaoQing Chen, Darrell Bessette, Kelli MacDonald, Sunil R. Lakhani, Georgia Chenevix-Trench, Kara Britt, Fares Al-Ejeh |
| Rok vydání: |
2023 |
| Popis: |
BackgroundGenome-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 ofKCNN4.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.MethodsWe evaluated public mRNA expression data to determine whether the allele at 19q13.31 associated with increased breast cancer risk was associated withKCNN4expression. We also used immunohistochemistry to evaluate the relationship between KCNN4 protein expression and breast cancer survival. We then used Senicapoc in two murine mammary tumor models to determine if it would delay tumor development. We also treated mice bearing 4T1 mammary tumors with Senicapoc, by subcutaneous injection and by oral gavage. Finally we used gene editing to make deletions withinKcnn4in 4T1 to determine whether Senicapoc had off-target effects on tumor growth.ResultsAnalysis of the Genotype-Tissue Expression Project showed that the allele at 19q13.31 associated with increased breast cancer risk is associated with increasedKCNN4expression, suggesting that inhibiting KCNN4 might reduce breast cancer risk. Using immunohistochemistry in a large breast cancer cohort, we found that membrane and cytoplasmic expression is a marker of poor prognosis in triple negative breast cancer. We then tested the efficacy of Senicapoc to prevent and treat breast cancer. This showed that it delays the development of mammary tumors in two murine models, and slows growth of a syngeneic (4T1) model of triple negative breast cancer. Senicapoc monotherapy showed similar efficacy to anthracycline/taxane-based chemotherapy in these studies, with a stronger effect when they were combined.ConclusionsThese results provide a rationale for clinical testing of Senicapoc for treating, and even preventing, breast cancer. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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