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The role of Gremlin1 in breast cancer disease progression: relevant molecular and cellular mechanisms

Zabkiewicz, Catherine 2021. The role of Gremlin1 in breast cancer disease progression: relevant molecular and cellular mechanisms. PhD Thesis, Cardiff University.
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Abstract

Bone Morphogenetic Proteins (BMPs) are members of the Transforming Growth Factor Beta (TGFβ) family, that were discovered for their role in bone development, but have since been found to regulate cellular differentiation and tissue homeostasis. The cellular effect of BMPs is highly regulated, involving secreted antagonist proteins that directly bind BMPs, dampening BMP signalling. BMPs and their antagonists are of interest for their role in tumourigenesis and metastasis in cancer. Due to their significance in bone homeostasis, they are of particular interest in breast cancer, which commonly metastasises to bone. Despite progress in treatment and outcomes, those with metastatic breast cancer have poor survival. A better understanding of breast cancer biology, and development of prognostic markers and therapeutic targets is required for improved patient outcomes. The Gremlin1 ligands BMP-2, -4 and -7, have been implicated in breast cancer disease progression, but little is known regarding the role of Gremlin1 itself. This work determined that Gremlin1 expression in breast cancer is upregulated, but that its impact is dependent on the subtype and receptor profile of the breast cancer. There is a strong correlation between Gremlin1 and the Human Epidermal Growth Factor Receptor 2 (HER2), wherein upregulated Gremlin1 is a negative prognostic marker. Upregulation of Gremlin1 in HER2+ breast cancer cells increased proliferation, migration, and markers of epithelial to mesenchymal transition (EMT). In vivo Gremlin1 promoted HER2+ tumour growth and metastasis (particularly to bone). Inhibition of HER2 kinase activity abrogated the effect of Gremlin1 overexpression in vitro, suggesting a reciprocal relationship between Gremlin1 and HER2. Gremlin1 was also found to increase activity in AKT signalling and upregulates expression of PI3KCA, both important HER2 signalling pathway components. This highlights Gremlin1 as of relevance to HER2+ breast cancers, with a potential role in disease progression and response to HER2 blockade treatments.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 31 May 2022
Last Modified: 04 Aug 2022 01:37
URI: https://orca.cardiff.ac.uk/id/eprint/150056

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