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

Hayat, A; Carter, EP; King, HW; Ors, A; Doe, A; Teijeiro, SA; Charrot, S; Godinho, S; Cutillas, P; Mohammed, H; Grose, RP; Ficz, G

Author(s): Hayat, A; Carter, EP; King, HW; Ors, A; Doe, A; Teijeiro, SA; Charrot, S; Godinho, S; Cutillas, P; Mohammed, H; Grose, RP; Ficz, G;
Details: Publication Year 2023-02-01,Volume 16,Issue #2,Page dmm049894
Journal Title: Disease Models & Mechanisims
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.
Publisher: COB
Keywords: Humans; *Chromatin; *Receptor, ErbB-2/genetics; Cell Proliferation; Cell Transformation, Neoplastic/genetics; Epithelium/metabolism; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; In vitro; Breast; Cancer; Chromatin; Epigenetics; Stem
Research Division(s): Epigenetics And Development
PubMed ID: 36661191/
Publisher's Version: https://doi.org/10.1242/dmm.049894
Open Access at Publisher's Site: https://doi.org/10.1242/dmm.049894
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: dmm049894.pdf - (3.66MB, application/pdf)

Creation Date: 2023-11-30 09:13:28

Last Modified: 2023-11-30 09:24:36