Phenotypic and transcriptomic alterations associated with enhanced metastatic potential in breast cancer
AffiliationPharmacology and Therapeutics
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2021-10-29.
© 2018 Yan Tu
Despite current advances in therapies and the gradual decline in breast cancer-related mortality, metastasis is the major determinant of breast cancer survival. The treatment regimens for breast cancer metastasis are complicated by the unpredictability of metastasis development, as well as the inter- and intra-tumour heterogeneity observed in breast cancer patients. Therefore, the diagnosis and management of metastatic disease remains a major therapeutic challenge for breast cancer treatment. To overcome these obstacles, full understanding of the molecular mechanism that governs the process of metastasis is urgently needed. Annexin A1 is a protein well known for its anti-inflammatory biology and also demonstrated convincing, though controversial influences on breast cancer progression. Accumulating evidence suggest that the influence of annexin A1 may only manifest in the most aggressive breast tumour and investigation of this relationship needs to be conducted in models that reflect this specificity A powerful model developed to effectively study the complexities associated with breast cancer metastasis are breast cancer variant cell lines derived from the same parental line but displaying differing in metastatic capabilities. The MDA-MB-231HM.LNm5 is a one of such novel cell lines derived by in vivo passaging of the TN human breast adenocarcinoma MDA-MB-231 line and demonstrated robust metastatic propensity. Using this cellular model of metastasis, the body of work presented in this thesis attempted to investigate the mechanisms underlying the acquisition of metastatic phenotype in both a hypothesis and a non-hypothesis-driven manner. Part one of this thesis aimed to describe some of the phenotypic, molecular, and transcriptomic changes associated with enhanced metastatic potential found in the MDA-MB-231HM.LNm5 line, including changes in energy metabolism, proliferation, and growth-related processes. In the second part of this thesis, the endogenous expression of annexin A1 in the MDA-MB-231HM.LNm5 cells line and the parental line was silenced to explore the influence of annexin A1 on characteristics associated with elevated metastatic potential. Finally, by manipulating tumour and host ANXA1 levels, as well the host immune system, we attempted to unravel the involvement of ANXA1 in tumour initiation, growth and metastasis in vivo. Accompanying the aggressive in vivo metastasis phenotype, the MDA-MB-231HM.LNm5 metastatic daughter line exhibits heightened energy metabolism and chemo-resistance but reduced in vitro proliferative propensity. This ‘go or grow’ dichotomy, underlined by an increase in the quiescent cell population and dampened Ca2+ signalling, can be restored by the knock-down of ANXA1. In comparison, phenotypes of the non-metastatic parental MDA-MB-231 cells are unaltered by ANXA1 KD. In vivo studies showed that the expression of annexin A1 is required for growth and progression of breast cancer in specific metastatic mouse models. Overall, the studies presented in this thesis deepens our knowledge of the complex biological processes underlying the acquisition of metastatic propensity in breast cancer and reported evidence that suggested annexin A1 to be an important contributor of metastatic alterations. Further targeted investigation could facilitate the development of new strategies for therapeutic interventions and clinical management of patients with metastatic breast cancer
KeywordsBreast cancer; energy reprogramming; cancer metabolism; metastasis; RNA-seq; animal models; annexin A1; proliferation
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