Identification of cellular and genetic drivers of breast cancer heterogeneity in genetically engineered mouse tumour models

Melchor, Lorenzo, Molyneux, Gemma, Mackay, Alan, Magnay, Fiona-Ann, Atienza, María, Kendrick, Howard, Nava-Rodrigues, Daniel, López-García, María Ángeles, Milanezi, Fernanda, Greenow, Kirsty, Robertson, David, Palacios, José, Reis-Filho, Jorge S. and Smalley, Matthew J. ORCID: https://orcid.org/0000-0001-9540-1146 2014. Identification of cellular and genetic drivers of breast cancer heterogeneity in genetically engineered mouse tumour models. Journal of Pathology 233 (2) , pp. 124-137. 10.1002/path.4345

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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 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	Brca2;Pten;p53;tumour heterogeneity;breast cancer molecular subtypes;basal-like
Additional Information:	This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Publisher:	Wiley
ISSN:	0022-3417
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	26 February 2014
Last Modified:	07 Nov 2023 16:03
URI:	https://orca.cardiff.ac.uk/id/eprint/58468

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