Inhibition of AKT suppresses the initiation and progression of BRCA1-associated mammary tumors
- Authors
- Baek, Hye Jung; Kim, Sun Eui; Kim, Jong Kwang; Shin, Dong Hoon; Kim, Tae Hyun; Kim, Kwang Gi; Deng, Chu-Xia; Kim, Sang Soo
- Issue Date
- Oct-2018
- Publisher
- IVYSPRING INT PUBL
- Keywords
- BRCA1; AKT; MK-2206; precision medicine
- Citation
- INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES, v.14, no.13, pp.1769 - 1781
- Journal Title
- INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
- Volume
- 14
- Number
- 13
- Start Page
- 1769
- End Page
- 1781
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/5305
- DOI
- 10.7150/ijbs.29242
- ISSN
- 1449-2288
- 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 Aka in Brca1-mutant mouse model significantly decreased mammary tumor formation from 54% in Brca1(co/co)MMTV-Cre mice to 22% in Brca1(co/co)MMTV-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.
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