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Int J Biol Sci. 2018 Oct 3;14(13):1769-1781. doi: 10.7150/ijbs.29242. eCollection 2018.

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

Author information

1
Research Institute, National Cancer Center, Goyang, 10408, Korea.
2
Department of Biomedical Engineering, Gachon University College of Medicine, Incheon, 21565, Korea.
3
Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR 999078, China.

Abstract

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 Brca1co/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.

KEYWORDS:

AKT; BRCA1; MK-2206; precision medicine

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