Identification of cellular and genetic drivers of breast cancer heterogeneity in genetically engineered mouse tumour models
| Autor: | Matthew J. Smalley, Howard Kendrick, José Palacios, Alan Mackay, Kirsty Rhian Greenow, María Ángeles López-García, Maria A. Atienza, Fiona-Ann Magnay, Jorge S. Reis-Filho, Lorenzo Melchor, Fernanda Milanezi, Gemma Molyneux, Daniel Nava-Rodrigues, David J. Robertson |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Pathology
medicine.medical_specialty Time Factors Tumour heterogeneity Breast Neoplasms Disease Biology Pathology and Forensic Medicine Mice Mammary Glands Animal Breast cancer medicine Animals Humans PTEN Genetic Predisposition to Disease Gene Cell Proliferation BRCA2 Protein Mice Knockout Carcinoma Ductal Breast PTEN Phosphohydrolase Epithelial Cells medicine.disease Phenotype R1 Epithelium Gene Expression Regulation Neoplastic Disease Models Animal Cell Transformation Neoplastic medicine.anatomical_structure Receptors Estrogen Genetically Engineered Mouse Claudins biology.protein Female Tumor Suppressor Protein p53 |
| ISSN: | 0022-3417 |
| Popis: | The heterogeneous nature of mammary tumours may arise from different initiating genetic lesions occurring in distinct cells of origin. Here, we generated mice in which Brca2, Pten and p53 were depleted in either basal mammary epithelial cells or luminal oestrogen receptor (ER) negative cells. Basal cell-origin tumors displayed similar histological phenotypes regardless of the depleted gene. In contrast, luminal ER negative cells gave rise to diverse phenotypes, depending on the initiating lesions, including both ER negative and, strikingly, ER positive Invasive Ductal Carcinomas. Molecular profiling demonstrated that luminal ER negative cell-origin tumours resembled a range of the molecular subtypes of human breast cancer, including basal-like, luminal B and ‘normal-like’. Furthermore, a subset of these tumours resembled the ‘claudin-low’ tumour subtype. These findings demonstrate that not only do mammary tumour phenotypes depend on the interactions between cell-of-origin and driver genetic aberrations, but also that multiple mammary tumour subtypes, including both ER positive and negative disease, can originate from a single epithelial cell type. This is a fundamental advance in our understanding of tumour etiology. |
| Databáze: | OpenAIRE |
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