Premium
Identification of cellular and genetic drivers of breast cancer heterogeneity in genetically engineered mouse tumour models
Author(s) -
Melchor Lorenzo,
Molyneux Gemma,
Mackay Alan,
Magnay FionaAnn,
Atienza María,
Kendrick Howard,
NavaRodrigues Daniel,
LópezGarcía María Ángeles,
Milanezi Fernanda,
Greenow Kirsty,
Robertson David,
Palacios José,
ReisFilho Jorge S,
Smalley Matthew J
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4345
Subject(s) - phenotype , biology , pten , cancer research , genetic heterogeneity , cell , breast cancer , mammary gland , basal (medicine) , pathology , gene , cancer , microbiology and biotechnology , genetics , signal transduction , medicine , pi3k/akt/mtor pathway , endocrinology , insulin
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 tumours 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 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 aetiology. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.