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

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 subty...

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Bibliographic Details
Published in:Disease models & mechanisms 2023-02, Vol.16 (2)
Main Authors: Hayat, Ateequllah, Carter, Edward P, King, Hamish W, Ors, Aysegul, Doe, Aaron, Teijeiro, Saul A, Charrot, Sarah, Godinho, Susana, Cutillas, Pedro, Mohammed, Hisham, Grose, Richard P, Ficz, Gabriella
Format: Article
Language:English
Subjects:
breast
Breast cancer
cancer
Cell culture
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic - genetics
Cells
Chromatin
epigenetics
Epithelium
Epithelium - metabolism
ErbB-2 protein
Gene Expression Regulation, Neoplastic
Genetic transformation
Humans
in vitro
Kinases
Metastasis
Phenotypes
Phosphorylation
Protein expression
Proteins
Receptor, ErbB-2 - genetics
Regulatory sequences
Statistical significance
stem
Student's t-test
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Summary: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.
ISSN:1754-8403
1754-8411
DOI:10.1242/dmm.049894