Unknown,Transcriptomics,Genomics,Proteomics

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Targeted Pten deletion plus p53-R270H mutation in mouse mammary epithelium induces aggressive claudin-low and basal-like breast cancer

ABSTRACT: WAP-Cre:Ptenf/f:p53lox.stop.lox_R270H composite mice were generated by genetic crossing. In these mice, Pten is deleted and a R270H p53 mutation in the DNA binding domain is induced upon expression of Cre recombinase in pregnancy-identified alveolar progenitors. Tumors were characterized by histology, marker analysis, various bioinformatics methods, high-throughput (HTP) FDA-drug screen as well as orthotopic injection to quantify tumor initiating cells (TICs) and tail-vein injection to identify lung-metastasis. Expression data comparing 2 types of Pten-deficient tumors (spindle and poorly differentiated) with other modles of mouse mammary tumors 2 types of Pten deletion plus p53-R270H mutation tumors (spindle and poorly differentiated) was compared with MMTV-Neu, Spindle Pten-p53-deficient tumors, and wild-type mammary gland cells.

ORGANISM(S): Mus musculus

SUBMITTER: Jeff Liu

PROVIDER: E-GEOD-75989 | 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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Targeted Pten deletion plus p53-R270H mutation in mouse mammary epithelium induces aggressive claudin-low and basal-like breast cancer

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