A system biology study of the molecular mechanism of Metformin on breast cancer

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Al-Juboori, S.I.K., 2019. A system biology study of the molecular mechanism of Metformin on breast cancer. PhD, Nottingham Trent University.

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Abstract

Breast cancer is a complicated, heterogeneous and diversified disease that comprises of a mixture of various subtypes. The emergence of high throughout technologies such as gene expression profiling and DNA copy number analysis has allowed a profound awareness of this complex disease. Breast cancer molecular classification began with ER, PR and HER2 based stratification of patients, and further classified into various intrinsic subtypes such as Luminal A, Luminal B, Her-2 enriched, Basal-like, and Claudin-low. These subtypes were proven to have significant divergences in amplified and mutated genes, survival rates, prognosis and response to therapy.

The anti-diabetic drug Metformin has been prescribed to treat type 2 diabetes patients since 1957 with a well-established side effects and safety profile. Additionally, cancer researchers have studied the anti-tumour effects of this drug since 2005 and have determined Metformin benefit in the reduction of cancers incidence. Thus, Metformin has been suggested as an ideal candidate to treat and prevent diverse types of cancers, including breast carcinoma.

The purpose of this study is to elucidate the biological and molecular effects of Metformin on breast cancer cell lines such as BT-474, MCF-7, MDA-MB-231, MDA-MB-468, and SkBr3.

Interestingly, Metformin treatments reduced the viability and proliferation of examined breast cancer cell lines, while induced cells apoptosis. Basal-like (MDA-MB-468) was the most sensitive phenotype to Metformin treatments, whereas HER2 (SkBr3) was the least sensitive subtype.

We performed Gene Expression Microarray and NanoString analysis of Metformin treated MDAMB- 468 and SkBr3 cells and found that the upregulated Protein Tyrosine Kinase 2 Beta (PTK2B) was predominantly involved in cell proliferation, cell survival, cell migration and cell invasion.

We found that PTK2B promotes invasion and migration, while prevents the proliferation of breast cancer cells. It is also, playing a vital role in Autocrine Somatotropin signalling pathway in breast cancer. Additionally, Mass Spectrometry (MS) analyses and pathways enrichment analysis that has emphasised the role of PTK2B in breast cancer invasion and metastasis. Additionally, the combined action of both selected markers and Metformin treatment on fundamental biological functions in breast cancer were also assessed.

These data showed that Metformin promotes Her-2 enriched breast cancer invasion through mechanisms involving PYK2, and that future treatments should consider potential complications resulting from metformin-based therapies.

Item Type:	Thesis
Creators:	Al-Juboori, S.I.K.
Date:	July 2019
Rights:	This work is the intellectual property of the author. You may copy up to 5% of this work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed to the owner(s) of the Intellectual Property Rights.
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	25 Jul 2019 09:45
Last Modified:	25 Jul 2019 09:45
URI:	https://irep.ntu.ac.uk/id/eprint/37143