Cooperativity of Rb, Brca1, and p53 in malignant breast cancer evolution

Autor: Jacob P. S. Johnson, Prashant Kumar, Malini Mukherjee, Milan K. Patel, Karl Simin, Bing Huey, Donna G. Albertson
Rok vydání: 2012
Předmět:
Cancer Research
Mouse
Receptor
ErbB-2
Gene Expression
Apoptosis
Retinoblastoma Protein
Mice
Metaplasia
Breast Tumors
Basic Cancer Research
Genetics (clinical)
Regulation of gene expression
biology
BRCA1 Protein
Systems Biology
Retinoblastoma protein
Genomics
Animal Models
Gene Expression Regulation
Neoplastic
medicine.anatomical_structure
Oncology
Medicine
Female
medicine.symptom
Receptors
Progesterone
Metabolic Networks and Pathways
Research Article
Programmed cell death
lcsh:QH426-470
Breast Neoplasms
Evolution
Molecular
Molecular Genetics
Breast cancer
Mammary Glands
Animal
Model Organisms
medicine
Biomarkers
Tumor
Genetics
Animals
Humans
Involution (medicine)
Molecular Biology
Biology
Ecology
Evolution
Behavior and Systematics
Estrogen Receptor alpha
Computational Biology
Cancers and Neoplasms
Comparative Genomics
medicine.disease
Epithelium
lcsh:Genetics
Cancer research
biology.protein
Tumor Suppressor Protein p53
Estrogen receptor alpha
Animal Genetics
Zdroj: PLoS Genetics
PLoS Genetics, Vol 8, Iss 11, p e1003027 (2012)
ISSN: 1553-7404
Popis: Breast cancers that are “triple-negative” for the clinical markers ESR1, PGR, and HER2 typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that the combined inactivation of Rb and p53 pathways is sufficient to suppress the physiological cell death of mammary involution. Furthermore, concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency and predisposes highly penetrant, metastatic adenocarcinomas. The tumors are poorly differentiated and have histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Gene expression analyses demonstrate that the tumors share attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader, triple-negative class defined by clinical markers.
Author Summary These studies establish a unique animal model of aggressive forms of breast cancer for which there are no effective, targeted treatments. Rb, p53, and Brca1 are associated with inherited forms of cancer, but defects in these pathways are also found together in a subset of breast cancer patients without a family history of the disease. Simultaneous inactivation of all three pathways causes more aggressive disease than do pair-wise combinations, indicating that the pathways play non-overlapping roles in tumor prevention.
Databáze: OpenAIRE
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