Identification of Cellular and Genetic Drivers of Breast Cancer Heterogeneity in Genetically Engineered Mouse Tumour Models

J Pathol. 2014 Jun;233(2):124-37. doi: 10.1002/path.4345.

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.

Keywords: Brca2; Pten; basal-like; breast cancer molecular subtypes; p53; tumour heterogeneity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA2 Protein / deficiency
  • BRCA2 Protein / genetics*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / genetics*
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / pathology
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Claudins / metabolism
  • Disease Models, Animal
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genetic Predisposition to Disease
  • Humans
  • Mammary Glands, Animal / metabolism*
  • Mammary Glands, Animal / pathology
  • Mice
  • Mice, Knockout
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / genetics*
  • Phenotype
  • Receptors, Estrogen / metabolism
  • Time Factors
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • BRCA2 Protein
  • BRCA2 protein, mouse
  • Claudins
  • Receptors, Estrogen
  • Tumor Suppressor Protein p53
  • PTEN Phosphohydrolase
  • Pten protein, mouse