Molecular and cellular concept of Noggin in the personalised disease management of breast cancer

Liu, Ming 2024. Molecular and cellular concept of Noggin in the personalised disease management of breast cancer. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Bone morphogenetic proteins (BMPs) are actively involved in cancer development and metastasis of solid tumours, especially in breast cancer. BMPs are functional in cell differentiation, proliferation, invasion and metastasis in breast cancer cells. BMPs have been reported to play dual roles in malignant tumours. However, the specific roles of breast cancer sub-type are still poorly understood. As an antagonist of BMP, increased Noggin expression contributes to bone metastasis in breast cancer. However, its role in different subtypes of the disease remains largely unknown. In this study, it was found that aberrant expression of Noggin was revealed in different subtypes of breast cancer, which was associated with poor prognosis. In ER positive subtype, Noggin expression was repressed by an oestrogen-induced interruption of BMP-Smad signalling. Noggin overexpression conferred a resistance of ER positive breast cancer cells to both tamoxifen (TAM) and chemotherapy. Noggin promoted invasiveness and migration through upregulation of EGFR/ERK in TNBC cells. In HER2 positive breast cancer cells, Noggin promoted proliferation and invasion through up-regulation of HER2 and its downstream MAPK/ERK signalling pathway. On the other hand, the expression of Noggin was increased following knockdown of HER2 or blockage with a HER2 inhibitor (CP724714). Furthermore, proteomics analysis revealed that PFKP was the only commonly up-regulated protein investigated in both BT474 and HCC1419 HER2 expressing breast cancer cell lines. Moreover, by analysing phosphorylated proteins, certain pathways were highlighted for a possible role in Noggin regulated molecular and cellular events, in HER2 expressing breast cancer cells, which included the TGF-β pathway, BMP-Smad dependent and independent pathways and the Wnt/βcatenin pathway, although further validation is required. In conclusion, higher expression of Noggin is associated with poor survival of breast cancer patients. Noggin regulates proliferation, migration and invasion of breast cancer cells in a subtype specific fashion, by interacting with ER, HER2, EGFR, BMPs and BMP signalling. Noggin may serve as a subtype specific marker and novel target for the personalised disease management of breast cancer.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	12 January 2024
Last Modified:	12 Jan 2024 10:14
URI:	https://orca.cardiff.ac.uk/id/eprint/165418

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