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

Research Paper

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

Hye Jung Baek^1*, Sun Eui Kim^1*, Jong Kwang Kim^1*, Dong Hoon Shin¹, Tae Hyun Kim¹, Kwang Gi Kim², Chu-Xia Deng³, Sang Soo Kim^1✉

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.
^*These authors contributed equally.

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 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.

Keywords: BRCA1, AKT, MK-2206, precision medicine