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Comparative oncogenomics identifies breast tumors enriched in functional tumor-initiating cells.

Abstract：

:The claudin-low subtype is a recently identified rare molecular subtype of human breast cancer that expresses low levels of tight and adherens junction genes and shows high expression of epithelial-to-mesenchymal transition (EMT) genes. These tumors are enriched in gene expression signatures derived from human tumor-initiating cells (TICs) and human mammary stem cells. Through cross-species analysis, we discovered mouse mammary tumors that have similar gene expression characteristics as human claudin-low tumors and were also enriched for the human TIC signature. Such claudin-low tumors were similarly rare but came from a number of distinct mouse models, including the p53 null transplant model. Here we present a molecular characterization of 50 p53 null mammary tumors compared with other mouse models and human breast tumor subtypes. Similar to human tumors, the murine p53 null tumors fell into multiple molecular subtypes, including two basal-like, a luminal, a claudin-low, and a subtype unique to this model. The claudin-low tumors also showed high gene expression of EMT inducers, low expression of the miR-200 family, and low to absent expression of both claudin 3 and E-cadherin. These murine subtypes also contained distinct genomic DNA copy number changes, some of which are similarly altered in their cognate human subtype counterpart. Finally, limiting dilution transplantation revealed that p53 null claudin-low tumors are highly enriched for TICs compared with the more common adenocarcinomas arising in the same model, thus providing a unique preclinical mouse model to investigate the therapeutic response of TICs.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Herschkowitz JI,Zhao W,Zhang M,Usary J,Murrow G,Edwards D,Knezevic J,Greene SB,Darr D,Troester MA,Hilsenbeck SG,Medina D,Perou CM,Rosen JM

doi

10.1073/pnas.1018862108

subject

Has Abstract

pub_date

2012-02-21 00:00:00

pages

2778-83

issue

eissn

0027-8424

issn

1091-6490

pii

1018862108

journal_volume

109

pub_type

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Comparative oncogenomics identifies breast tumors enriched in functional tumor-initiating cells.