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Induced p53 loss in mouse luminal cells causes clonal expansion and development of mammary tumours
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Induced p53 loss in mouse luminal cells causes clonal expansion and development of mammary tumours
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Journal Article
Induced p53 loss in mouse luminal cells causes clonal expansion and development of mammary tumours
2017
Overview
Most breast cancers may have a luminal origin.
TP53
is one of the most frequently mutated genes in breast cancers. However, how p53 deficiency contributes to breast tumorigenesis from luminal cells remains elusive. Here we report that induced p53 loss in
Krt8
+
mammary luminal cells leads to their clonal expansion without directly affecting their luminal identity. All induced mice develop mammary tumours with 9qA1 (
Yap1
) and/or 6qA2 (
Met
) amplification(s). These tumours exhibit a mammary stem cell (MaSC)-like expression signature and most closely resemble claudin-low breast cancer. Thus, although p53 does not directly control the luminal fate, its loss facilitates acquisition of MaSC-like properties by luminal cells and predisposes them to development of mammary tumours with loss of luminal identity. Our data also suggest that claudin-low breast cancer can develop from luminal cells, possibly via a basal-like intermediate state, although further study using a different luminal promoter is needed to fully support this conclusion.
Several breast cancers may originate from mammary luminal cells and inactivating mutations of p53 are present in most triple-negative breast cancers. Here, the authors show that loss of p53 from luminal cells in mice results in their clonal expansion and mammary tumour formation.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/100
/ 13/31
/ 13/51
/ 14/35
/ 14/63
/ 38/61
/ 38/77
/ 42/44
/ 64/110
/ Adaptor Proteins, Signal Transducing - genetics
/ Animals
/ Cell Proliferation - genetics
/ Cell Transformation, Neoplastic - genetics
/ Female
/ Females
/ Humanities and Social Sciences
/ Humans
/ Mammary Glands, Animal - metabolism
/ Mammary Neoplasms, Animal - genetics
/ Mutation
/ Proto-Oncogene Proteins c-met - genetics
/ Science
/ Tumor Suppressor Protein p53 - genetics
/ Tumors
