Activation of Akt1 accelerates carcinogen-induced tumorigenesis in mammary gland of virgin and post-lactating transgenic miceReport as inadecuate

Activation of Akt1 accelerates carcinogen-induced tumorigenesis in mammary gland of virgin and post-lactating transgenic mice - Download this document for free, or read online. Document in PDF available to download.

BMC Cancer

, 14:266

Cell and molecular biology


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.

KeywordsMyr-Akt1 Tumorigenesis Mammary gland Estrogen Lactation Breast cancer Abbreviationsmyr-Akt1myristoylated-Akt1

DMBA7, 12 dimethyl-1,2-benzanthracene

MMTV-LTRMouse Mammary Tumor Virus Long Terminal Repeat Promoter

CMVCytomegalovirus immediate-early promoter


EGFREpidermal growth factor receptor

EREstrogen receptor

PRProgesterone receptor

HER2Human Epidermal Growth Factor Receptor 2

EMTEpithelial-mesenchymal transition.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-14-266 contains supplementary material, which is available to authorized users.

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Author: Yanyuan Wu - Juri Kim - Yayha Elshimali - Marianna Sarkissyan - Jaydutt V Vadgama



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