The role of systemic and local inflammation, the tumour microenvironment and the IL6/JAK/STAT3 pathway in primary operable breast cancer

Morrow, Elizabeth (2021) The role of systemic and local inflammation, the tumour microenvironment and the IL6/JAK/STAT3 pathway in primary operable breast cancer. PhD thesis, University of Glasgow.

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Breast cancer is the second most common cause of cancer death in females in the UK. It is a heterogenous disease with subtypes which behave differently. There are targeted treatments available for luminal and HER2+ cancers but treatment resistance and cancer recurrences occur. There are currently no targeted treatments for triple negative breast cancer (TNBC). New prognostic tools to stratify risk to guide use of the most aggressive treatments, and new therapeutic targets are desirable. The role of the tumour microenvironment in tumour progression is increasingly recognised. Features of the tumour such as necrosis and budding have been reported to have a prognostic role in cancer and may be influenced by the tumour microenvironment. Cell signalling pathways such as the IL6/JAK/STAT3 pathway provide a link between the tumour microenvironment and tumour cells. Better understanding of these features and pathways may lead to identification of new prognostic and predictive tools and of new therapeutic targets.

The work of this thesis is carried out in two cohorts of patients with primary operable breast cancer with mature follow up. Data was available from clinical records for both regarding patient age, tumour pathology, treatment details and survival. Full section slides from surplus tissue were available from both cohorts and a tissue microarray (TMA) had been previously constructed for the largest cohort. The majority of the work in this thesis is carried out using haematoxylin and eosin (H&E)-stained full section slides and TMA slides stained using immunohistochemistry (IHC) techniques for various proteins. Staining for IL6 expression was carried out using RNA scope. Transcriptomics was carried out using TempOSeq to identify genes associated with tumour budding.

The work of this thesis describes a new combined score of tumour necrosis, budding and tumour-stroma percentage (TSP) which has prognostic value in primary operable breast cancer. It identifies a poor prognostic group in oestrogen receptor positive (ER+) disease which could be targeted for more aggressive treatment, and stratifies risk in ER- disease. 9 genes of potential interest for further investigation are identified as being associated with the high budding phenotype in ER- cancers. For the first time in the literature, this work will describe, in luminal A cancers, an association between tumour IL6 and membranous IL6R expression and worse cancer specific survival (CSS), and an association between pSTAT3(Ser727) and improved CSS, indicating potential roles as prognostic markers in this subtype. It will describe the expression and associations with survival of other members of the pathway, informing further research regarding in which subtypes inhibiting targets in the pathway may be of clinical value.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Supervisor's Name: Edwards, Professor Joanne, Roseweir, Dr. Antonia and Romics, Mr. Laszlo
Date of Award: 2021
Depositing User: Theses Team
Unique ID: glathesis:2021-82458
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 23 Sep 2021 12:35
Last Modified: 23 Sep 2021 12:38
Thesis DOI: 10.5525/gla.thesis.82458

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