title: Activation of Akt1 accelerates carcinogen-induced tumorigenesis in mammary gland of virgin and post-lactating transgenic mice.
abstract: BACKGROUND
  Data 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  In summary, the MMTVmyr-Akt1 transgenic mouse model could be useful to study mechanisms of ER-positive breast tumor development.
authors.forename: Yanyuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Juri
authors.initials: J
authors.lastname: Kim
authors.forename: Yayha
authors.initials: Y
authors.lastname: Elshimali
authors.forename: Marianna
authors.initials: M
authors.lastname: Sarkissyan
authors.affiliation: Division of Cancer Research and Training, Charles R, Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, CA 90059, USA. jayvadgama@cdrewu.edu.
authors.forename: Jaydutt V
authors.initials: JV
authors.lastname: Vadgama
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects* / Q000235:genetics; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D007774:Lactation; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; D015127:9,10-Dimethyl-1,2-benzanthracene; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
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