title: Identification of cellular and genetic drivers of breast cancer heterogeneity in genetically engineered mouse tumour models.
abstract: 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.
authors.affiliation: Division of Breast Cancer Research, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Melchor
authors.forename: Gemma
authors.initials: G
authors.lastname: Molyneux
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Fiona-Ann
authors.initials: FA
authors.lastname: Magnay
authors.forename: María
authors.initials: M
authors.lastname: Atienza
authors.forename: Howard
authors.initials: H
authors.lastname: Kendrick
authors.forename: Daniel
authors.initials: D
authors.lastname: Nava-Rodrigues
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: López-García
authors.forename: Fernanda
authors.initials: F
authors.lastname: Milanezi
authors.forename: Kirsty
authors.initials: K
authors.lastname: Greenow
authors.forename: David
authors.initials: D
authors.lastname: Robertson
authors.forename: José
authors.initials: J
authors.lastname: Palacios
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Smalley
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057167:Claudins / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D010641:Phenotype; D011960:Receptors, Estrogen / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
chemical_list: D024682:BRCA2 Protein; C106711:BRCA2 protein, mouse; D057167:Claudins; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Brca2; Pten; basal-like; breast cancer molecular subtypes; p53; tumour heterogeneity