Low HER2 expression in normal breast epithelium enables dedifferentiation and malignant transformation via chromatin opening

Ateequllah Hayat, Edward P Carter, Hamish W King, Aysegul Ors, Aaron Doe, Saul A Teijeiro, Sarah Charrot, Susana Godinho, Pedro Cutillas, Hisham Mohammed, Richard P Grose, Gabriella Ficz

Research output: Contribution to journalArticlepeer-review

5 Citations (SciVal)

Abstract

Overexpression of the HER2 protein in breast cancer patients is a predictor of poor prognosis and resistance to therapies. We used an inducible breast cancer transformation system that allows investigation of early molecular changes. HER2 overexpression to similar levels as those observed in a subtype of HER2-positive breast cancer patients induced transformation of MCF10A cells and resulted in gross morphological changes, increased anchorage-independent growth of cells, and altered the transcriptional programme of genes associated with oncogenic transformation. Global phosphoproteomic analysis during HER2 induction predominantly detected an increase in protein phosphorylation. Intriguingly, this correlated with chromatin opening, as measured by ATAC-seq on acini isolated from 3D cell culture. HER2 overexpression resulted in opening of many distal regulatory regions and promoted reprogramming-associated heterogeneity. We found that a subset of cells acquired a dedifferentiated breast stem-like phenotype, making them likely candidates for malignant transformation. Our data show that this population of cells, which counterintuitively enriches for relatively low HER2 protein abundance and increased chromatin accessibility, possesses transformational drive, resulting in increased anchorage-independent growth in vitro compared to cells not displaying a stem-like phenotype.

Original languageEnglish
Article numberdmm049894
JournalDisease Models and Mechanisms
Volume16
Issue number2
DOIs
Publication statusPublished - 1 Feb 2023

Bibliographical note

Funding Information:
The authors acknowledge financial support from a Cancer Research UK-Oregon Health and Science University Spark Award – Early Detection Scheme (application title: Delineating early transformational events in HER2 positive breast cancer; application reference: C50210/A27068), awarded to G.F. The authors also acknowledge financial support from a Leverhulme Trust postgraduate grant, awarded to A.H., E.P.C. and R.P.G. were supported by Cancer Research UK (A27781). Open Access funding provided by Queen Mary University of London. Deposited in PMC for immediate release.

Data availability
The original contributions presented in the study are included in the article and its supplementary information. The ATAC-seq datasets can be accessed through the genetics data repository Gene Expression Omnibus (GEO) using accession GSE205386. The mass spectrometry phosphoproteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE Project accession PXD034105.

Keywords

  • Humans
  • Chromatin
  • Receptor, ErbB-2/genetics
  • Cell Proliferation
  • Cell Transformation, Neoplastic/genetics
  • Epithelium/metabolism
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • In vitro
  • Stem
  • Breast
  • Epigenetics
  • Cancer

ASJC Scopus subject areas

  • Immunology and Microbiology (miscellaneous)
  • General Biochemistry,Genetics and Molecular Biology
  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)

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