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Loss of c-Jun NH2-Terminal Kinase in Mammary Epithelial Cells is Sufficient for Adenosquamous Tumor Formation

ABSTRACT: The JNK pathway has been implicated in breast cancer, both from human tumor sequencing studies and from mouse models. To see if JNK deletion is able to form tumors in mice, we crossed Mapk8 and Mapk9 conditional animals with the WAP-Cre expressing mouse to specifically delete JNK in luminal epithelial cells of the breast. We found that JNK suppresses tumors and that the loss of JNK leads to adenosquamous carcinoma formation. To understand the role of JNK in the mammary epithelium, we performed RNA sequencing and analyzed gene expression from tumor-derived cell lines. Several pathways were perturbed in the carcinoma cell lines. Our results demonstrate that loss of JNK alone is sufficient to cause tumor formation and they reveal a gene signature of adenosquamous tumors that can help in better understanding and treating the disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE100581 | GEO | 2018/05/29

REPOSITORIES: GEO

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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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Loss of c-Jun NH2-Terminal Kinase in Mammary Epithelial Cells is Sufficient for Adenosquamous Tumor Formation

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