Inhibition of AKT suppresses the initiation and progression of BRCA1-associated mammary tumors

摘要

Despite the high incidence of BRCA1-mutant breast cancer, few substantial improvements in preventing or treating such cancers have been made. Using a Brca1-mutant mouse model, we examined the contribution of AKT to the incidence and growth of Brca1-mutated mammary tumors. A haploinsufficiency of Akt1 in Brca1-mutant mouse model significantly decreased mammary tumor formation from 54% in Brca1^co/coMMTV-Cre mice to 22% in Brca1 ^co/coMMTV-Cre Akt1^+/- mice. Notably, treatment of tumor-bearing Brca1-mutant mice with the AKT-inhibitor, MK-2206, yielded partial response or stable disease up to 91% of mice in maximum response. MK-2206 treatment also significantly reduced tumor volume and delayed recurrence in allograft and adjuvant studies, respectively. A correlation analysis of MK-2206 responses with gene expression profiles of tumors at baseline identified seven genes that were differentially expressed between tumors that did and did not respond to MK-2206 treatment. Our findings enhance our understanding of the involvement of AKT signaling in BRCA1-deficient mammary tumors and provide preclinical evidence that targeted AKT inhibition is a potential strategy for the prevention and therapeutic management of BRCA1-associated breast cancer.