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Induced loss of p53 in mammary luminal cells leads to their clonal expansion and facilitates development of mammary tumours with loss of luminal identity

ABSTRACT: Induced loss of p53 in mammary luminal cells leads to their clonal expansion and facilitates development of mammary tumours with loss of luminal identity

PROVIDER: PRJNA310634 | ENA |

REPOSITORIES: ENA

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Induced p53 loss in mouse luminal cells causes clonal expansion and development of mammary tumours.

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Microarray expression profiling data for Trp53-null mammary epithelial cells and tumors from a mouse model with a K8+ luminal cell origin

Project description:Mammary epithelium is hierarchically organized, with multipotent basal mammary stem cells (MaSCs) producing both luminal and basal cells during development or upon transplantation. Recent studies suggested that most breast cancers might originate from luminal cells, and oncogenic events, such as ectopic expression of PIK3CAH1047R, could induce multipotency in committed luminal cells. p53 is the most commonly mutated gene in human breast cancer; in particular, its inactivating mutations are found in most triple-negative breast cancers, raising a question as to whether p53-loss plays a key role in acquisition of MaSC-like properties by luminal cells. By in situ lineage tracing, we found that induced loss of p53 in Keratin 8 (K8)+ luminal cells led to their clonal expansion, in part due to increased proliferation, but did not directly affect their luminal identity. Expansion of luminal cells, in particular oestrogen receptor-positive luminal cells, was observed 3-4 weeks after induced p53-loss, which was accompanied by increased expression of cell cycle genes and downregulation of genes related to immune microenvironment, p53 downstream pathway and apoptosis control. All induced mice eventually developed mammary tumours with 9qA1 (Yap1) amplification and/or 6qA2 (Met) amplification. The resulting tumours exhibited a MaSC-like expression signature and most closely resembled Claudin-Low breast cancer. Overall, these data suggest that 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 originate from luminal cells, possibly upon transition through a basal-like state.

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Transcription profiling by array of mouse mammary tumours

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Induced loss of p53 in mammary luminal cells leads to their clonal expansion and facilitates development of mammary tumours with loss of luminal identity

Project description:This SuperSeries is composed of the SubSeries listed below.

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Development of mammary luminal progenitor cells is controlled by the transcription factor STAT5A

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