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

doi:10.1242/dmm.049894

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

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

6 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 language	English
Article number	dmm049894
Journal	Disease Models and Mechanisms
Volume	16
Issue number	2
DOIs	https://doi.org/10.1242/dmm.049894
Publication status	Published - 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)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1242/dmm.049894Licence: CC BY

Cite this

Hayat, A., Carter, E. P., King, H. W., Ors, A., Doe, A., Teijeiro, S. A., Charrot, S., Godinho, S., Cutillas, P., Mohammed, H., Grose, R. P., & Ficz, G. (2023). Low HER2 expression in normal breast epithelium enables dedifferentiation and malignant transformation via chromatin opening. Disease Models and Mechanisms, 16(2), Article dmm049894. https://doi.org/10.1242/dmm.049894

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title = "Low HER2 expression in normal breast epithelium enables dedifferentiation and malignant transformation via chromatin opening",

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.",

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",

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

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.",

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doi = "10.1242/dmm.049894",

language = "English",

volume = "16",

journal = "Disease Models and Mechanisms",

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T1 - Low HER2 expression in normal breast epithelium enables dedifferentiation and malignant transformation via chromatin opening

AU - Hayat, Ateequllah

AU - Carter, Edward P

AU - King, Hamish W

AU - Ors, Aysegul

AU - Doe, Aaron

AU - Teijeiro, Saul A

AU - Charrot, Sarah

AU - Godinho, Susana

AU - Cutillas, Pedro

AU - Mohammed, Hisham

AU - Grose, Richard P

AU - Ficz, Gabriella

N1 - 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.

PY - 2023/2/1

Y1 - 2023/2/1

N2 - 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.

AB - 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.

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KW - Cell Proliferation

KW - Cell Transformation, Neoplastic/genetics

KW - Epithelium/metabolism

KW - Cell Line, Tumor

KW - Gene Expression Regulation, Neoplastic

KW - In vitro

KW - Stem

KW - Breast

KW - Epigenetics

KW - Cancer

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U2 - 10.1242/dmm.049894

DO - 10.1242/dmm.049894

M3 - Article

C2 - 36661191

SN - 1754-8403

VL - 16

JO - Disease Models and Mechanisms

JF - Disease Models and Mechanisms

IS - 2

M1 - dmm049894

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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