Abstract 74: Activation of Akt1 accelerates carcinogen-induced tumorigenesis in mammary gland of virgin and post-lactating transgenic mice

Abstract

Abstract Introduction The data from in vivo and in vitro studies suggest that activation of Akt regulates cell survival signaling and plays a key role in tumorigenesis. To explore oncogenic role of Akt1 in the development of mammary tumor, transgenic mice were created. Methods The transgenic mice were generated by expressing myristoylated-Akt1 (myr-Akt1) under the control of MMTV-LTR promoter. The carcinogen 7, 12 dimethyl-1,2-benzanthracene (DMBA) was used for inducing tumor formation. Results The MMTV driven myr-Akt1 transgene expression was detected primarily in mammary glands, uterus, and ovaries and the expression level increased significantly in lactating mice, suggesting the response was hormone dependent. The total expression level of Akt in the mammary gland was also high in these lactating mice. Interestingly, the expression of MMTVmyr-Akt1 in ovary of transgenic mice caused significant increase in circulating estrogen levels, even at post-lactating stage. Expression of myr-Akt1 in mammary glands alone did not increase tumor formation frequency. However, an increased susceptibility to the induction of mammary tumors by DMBA was observed in transgenic mice, especially in post-lactating mice. DMBA induced 42.9% of mammary tumors in post-lactating transgenic mice within 34 weeks, but none in post-lactating wild-type mice. The myr-Akt1 driven mammary tumors induced by DMBA had increased phosphorylated-Akt1 and showed strong expression of estrogen receptor (ERα) and EGFR. Cyclin D1 was more frequently up-regulated in mammary tumors from transgenic mice compared to tumors from wild-type mice. Overexpression of Cyclin D1, however, was not completely dependent on activated Akt1. Interestingly, mammary tumors that had metastasized to secondary sites had increased expression of twist and slug, but showed low expression of Cyclin D1. Conclusions In summary, activation of Akt1 in mammary gland accelerated carcinogen-induced tumorigenesis, especially in post-lactating mice. Citation Format: Yanyuan Wu, Juri Kim, Yayha Elshimali, Jaydutt V. Vadgama. Activation of Akt1 accelerates carcinogen-induced tumorigenesis in mammary gland of virgin and post-lactating transgenic mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 74. doi:10.1158/1538-7445.AM2014-74