Abstract
BackgroundData from in vivo and in vitro studies suggest that activation of Akt regulates cell survival signaling and plays a key role in tumorigenesis. Hence, transgenic mice were created to explore the oncogenic role of Akt1 in the development of mammary tumors.MethodsThe transgenic mice were generated by expressing myristoylated-Akt1 (myr-Akt1) under the control of the MMTV-LTR promoter. The carcinogen 7, 12 dimethyl-1,2-benzanthracene (DMBA) was used to induce tumor formation.ResultsThe MMTV driven myr-Akt1 transgene expression was detected primarily in the mammary glands, uterus, and ovaries. The expression level increased significantly in lactating mice, suggesting that the response was hormone dependent. The total Akt expression level in the mammary gland was also higher in the lactating mice. Interestingly, the expression of MMTVmyr-Akt1 in the ovaries of the transgenic mice caused significant increase in circulating estrogen levels, even at the post-lactation stage. Expression of myr-Akt1 in mammary glands alone did not increase the frequency of tumor formation. However, there was an increased susceptibility of forming mammary tumors induced by DMBA in the transgenic mice, especially in mice post-lactation. Within 34 weeks, DMBA induced mammary tumors in 42.9% of transgenic mice post-lactation, but not in wild-type mice post-lactation. The myr-Akt1 mammary tumors induced by DMBA had increased phosphorylated-Akt1 and showed strong expression of estrogen receptor (ERα) and epidermal growth factor receptor (EGFR). In addition, 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 low expression of Cyclin D1.ConclusionsIn summary, the MMTVmyr-Akt1 transgenic mouse model could be useful to study mechanisms of ER-positive breast tumor development.
Highlights
Data from in vivo and in vitro studies suggest that activation of Akt regulates cell survival signaling and plays a key role in tumorigenesis
We have recently demonstrated that activation of Akt1 in breast tumor cells in vitro, leads to inactivation of FOXO1 and a decrease in response or resistance to trastuzumab-induced growth inhibition in Human Epidermal Growth Factor Receptor 2 (HER2) overexpressing breast cancer cells [12]
Data from our current study demonstrated that the mice carrying the myr-Akt1 transgene in the mammary glands had accelerated carcinogeninduced tumorigenesis during the virgin and postlactation stages
Summary
Data from in vivo and in vitro studies suggest that activation of Akt regulates cell survival signaling and plays a key role in tumorigenesis. Akt has been shown to play a key role in cellular survival pathways by inhibiting apoptotic processes, inducing cell proliferation, and protein synthesis [1,2,3]. Akt is frequently constitutively active in many types of human cancers, such as breast, ovarian, and prostate [8,9,10] It has been demonstrated by our group and others that activated Akt in tumor cells are associated with high grade tumors, late stage of diagnosis, and poor outcome in patients [9,10]. Significant data from in vivo and in vitro studies suggest that activation of Akt regulates cell survival signaling and plays a key role in tumorigenesis. A few in vivo studies have explored the role of Akt in normal mammary development and tumorigenesis using transgenic mouse models [13,14,15,16], the mechanisms associated with the oncogenic role of Akt remains to be further elucidated
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