Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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The gain-of-function AKT1E17K allele is oncogenic in mouse mammary gland

ABSTRACT: The gain-of-function mutation in the pleckstrin homology domain of AKT1 (AKT1E17K) occurs in lung and breast cancer. By use of human cellular models and of a AKT1E17K transgenic Cre-inducible murine strain (R26-AKT1E17K mice) we have demonstrated that AKT1E17K is a bona-fide oncogene for lung epithelial cells. However, the role of AKT1E17K in breast cancer remains to be determined. Here, we report the generation and the characterization of a MMTV-CRE;R26-AKT1E17K mouse strain that expresses the mutant AKT1E17K allele in the mammary epithelium. We observed that R26AKT1E17K;MMTV-Cre mice presented a variety of proliferative alterations of the mammary epithelium that were classified as adenosis with low-to-high grade dysplasia. In addition, AKT1E17K stimulates the development of mammary tumors with incidence of 43%. Tumors were morphologically classified as ductal adenocarcinoma of medium-high grade though subsequent immunoistochemical characterization suggested they were of basal-like origin, being PR-/HER2-/ERα+ and CK8-/CK10-/CK5+/CK14+. We also observed that tumors expressing mutant AKT1E17K presented activation of the downstream signaling axis GSK3/cyclin D1 in mammary epithelium, in parallel with increased proliferation rate as demonstrated by cell number count and measurement of Ki67. In conclusion, AKT1E17K is a bona fidae oncogene that is able to initiate tumors at high efficiency in murine mammary epithelium in vivo.

ORGANISM(S): Mus musculus

SUBMITTER: Donatella Malanga

PROVIDER: E-MTAB-7388 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:To model the effect of Pten loss on breast cancer, we deleted Pten using a floxed allele and the deleter lines MMTV-Cre(NLST), which targets stem/bi-potent progenitor cells, and WAP-Cre, which targets CD24-positive, pregnancy-identified stem cells/alveolar progenitors. Mammary tumors were detected in WAP-Cre:Ptenf/f females with a latency of 15.2 months. By 18 months, nearly all mice had succumbed to cancer. MMTV-Cre:Ptenf/f mice developed mammary tumors after a longer latency of 26.4 months and reduced penetrance (70%) compared to WAP-Cre:Ptenf/f mice. Tumors from both models were heterogeneous, consisting primarily of differentiated adenocarcinoma (adenomyoepithelioma; ~70%) and adenosquamous carcinoma (20-25%). In addition, a small fraction of tumors was classified as acinar and poorly differentiated adenocarcinoma (4-7%) and adenosarcoma (3-4%). To test the consequences of combined Pten and p53 gene mutation on breast cancer, we deleted both genes via MMTV-Cre or WAP-Cre. Kaplan-Meier tumor free survival curves revealed that WAP-Cre:Ptenf/f:p53f/f and MMTV-Cre:Ptenf/f:p53f/f females developed tumors with reduced latency of 11.3 and 9.8 months, compared with 15.2, 26.4, and 16.9 months for single-mutant WAP-Cre:Ptenf/f, MMTV-Cre:Ptenf/f or MMTV-Cre:p53f/f mice, respectively. In contrast to the heterogeneity of Pten tumors and small percentage of adenosarcomas in these mice, ~70% of Pten:p53 lesions were histologically classified as adeno-sacrcomatoid-like or mesenchymal-like breast cancer, with the rest exhibiting mixed mesenchymal plus adenocarcinomas and differentiated adenocarcinomas. The adeno-sacrcomatoid-like tumors expressed the mesenchymal markers vimentin, K5, SMA, N-cadherin and desmin but not ER, as well as islands of luminal-like K18 expressing cells surrounded by a layer of K14-positive cells. We used microarrays to detect differentially expressed genes in the Pten:p53 double-knock-out vs Pten or p53 single deletions Total RNA was extracted from tumors developed by double Trizol method and hybridized on Affymetrix microarrays.

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The gain-of-function AKT1E17K allele is oncogenic in mouse mammary gland

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