Year: 2017
Type: dissertation
Abstract: Breast cancer is the most common cancer in women.Despite advances in treatment options, the spread of breast cancer to distant organs (metastasis) remains the major cause of morbidity and mortality in breast cancer patients.This is attributed primarily to the impairment of function in affected organs.Thus, there remains a vital need for better-targeted treatments that more effectively inhibit the development or progression of metastases.Pim-1 is a serine/threonine survival kinase that has been implicated in the development of metastasis in several haematological and solid cancers.However, little is known about its role in breast cancer.In our laboratory, we previously identified Pim-1 as upregulated in brain metastatic 4T1Br4 syngeneic mouse cells and tumours compared to parental 4T1 cells.This led us to propose that Pim-1 may play a role in mediating breast cancer brain metastasis.Therefore, the overall objective of this project was to examine the expression and functional role of Pim-1 in breast cancer metastasis, with a focus on organspecific metastasis.We interrogated public databases to show that Pim-1 expression is low to absent in normal breast tissue and increased in breast tumour tissue.Furthermore we show that the murine (4T1Br4) and human (MDA-MB-231Br) brain metastatic breast cancer cell lines and tumours demonstrate the highest expression of Pim-1 mRNA and protein.To investigate the function of Pim-1 in breast cancer metastasis we tested the impact of inhibiting Pim-1, either by gene knock down using short hairpin RNAs or the pharmacological inhibitor SGI-1776, on the ability of 4T1Br4 and MDA-MB-231Br cells to migrate and invade in vitro.4T1Br4 cells displayed increased migration and invasion propensity after Pim-1 knock down and this was coupled with a decrease in β4 integrin expression.Conversely, MDA-MB-231Br cells showed a decreased ability to migrate and invade after Pim-1 KD, as well as decreased cell surface expression of β1 and β3 integrins.The undertaking of a research project is undoubtedly a journey, filled with many trial and tribulations, as well as every pitfall and roadblock you could possibly imagine.However, the successes and new discoveries make it all most definitely worthwhile and are all the sweeter for it.Most of all, I could not have completed this thesis without the help and support of some very important people.
Author: Lara Jupp
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2753333132