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ISSN 1449-2288 |
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International Journal of Medical Sciences Journal of Bone and Joint Infection (JBJI) ![]() ![]() |
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 1. Research Institute, National Cancer Center, Goyang, 10408, Korea, 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: BRCA1, AKT, MK-2206, precision medicine This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
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to cite this article:
Baek HJ, Kim SE, Kim JK, Shin DH, Kim TH, Kim KG, Deng CX, Kim SS. Inhibition of AKT suppresses the initiation and progression of BRCA1-associated mammary tumors. Int J Biol Sci 2018; 14(13):1769-1781. doi:10.7150/ijbs.29242. Available from http://www.ijbs.com/v14p1769.htm |