Login (DCU Staff Only)
Login (DCU Staff Only)

DORAS | DCU Research Repository

Explore open access research and scholarly works from DCU

Advanced Search

Investigating the role of HER4 and HER4 mutations in cancer

Valenti, Marta (2025) Investigating the role of HER4 and HER4 mutations in cancer. PhD thesis, Dublin City University.

Dysregulation of the Human Epidermal growth factor Receptor (HER/ErbB) family is associated with tumorigenesis, however HER4’s role remains unclear. Unlike other HER family members (EGFR, HER2, HER3), HER4 presents four isoforms, with different stability and tissue-specific expression. This thesis examines the role of HER4 in cancer. Given the high frequency of HER4 point mutations in cancers such as cutaneous melanoma (CM) (17.34%) and gastroesophageal (GE) cancers (12.22%), models of these cancers were investigated for HER4/ERBB4 isoform expression and activation upon neuregulin stimulation. Additionally, HER4 was investigated in models of Atypical Teratoid Rhabdoid Tumour due to its potential role in this disease. HER4 expression was low/absent in the majority of cell lines investigated, with neuregulin stimulation being cell line-specific. Tissue microarrays of skin and CM samples were analysed for HER4 expression to assess variances between HER4 expression in in vitro models and patients. HER4 expression was higher in malignant and metastatic CM compared to skin samples. Using computational analyses, potentially oncogenic HER4 mutations in CM and GE cancers were identified. To functionally interrogate their impact in in vitro models, CRISPR/Cas9 methods were employed to insert HER4 mutations into CM cell lines. The successfully developed CRISPR/Cas9 HER4-edited CM cell lines reverted to HER4 WT. However, the analysis of a SKMEL24 CM HER4 CRISPR/Cas9 knockout suggested a potential role of HER4 in CM. Due to the interplay between oestrogen and HER4 in oestrogen receptor positive breast cancer and given the observed tendency for female CM patients to exhibit better outcomes than males, oestrogen stimulation was investigated as a potential mechanism that may influence CM tumour behaviour via the HER4 – GPER – RAR-α/RXR-γ axes. In conclusion, this thesis delivered novel insights into HER4 biology/function, identified a deficiency in availability of appropriate CM and GE HER4 cell line models, and developed a novel CM model to investigate HER4 biology.
Item Type:Thesis (PhD)
Date of Award:7 January 2025
Refereed:No
Supervisor(s):Collins, Denis M.
Subjects:Biological Sciences > Cell biology
Humanities > Biological Sciences > Cell biology
Biological Sciences > Molecular biology
Humanities > Biological Sciences > Molecular biology
Medical Sciences > Cancer
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health
DCU Faculties and Schools > Faculty of Science and Health > School of Biotechnology
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 License. View License
Funders:Science Foundation Ireland
ID Code:30633
Deposited On:06 Mar 2025 10:16 by Denis Collins . Last Modified 06 Mar 2025 10:16

Full text available as:

[thumbnail of Investigating the role of HER4 and HER4 mutations in cancer_Final thesis_Marta Valenti_20216088_without front page.pdf] PDF - Archive staff only. This file is embargoed until 2 February 2029 - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
14MB

Downloads

Downloads per month over past year

Archive Staff Only: edit this record