Browse DORAS
Browse Theses
Search
Latest Additions
Creative Commons License
Except where otherwise noted, content on this site is licensed for use under a:

The role of miRNAs in resistance to HER2 targeted therapies

Howe, Karen (2015) The role of miRNAs in resistance to HER2 targeted therapies. PhD thesis, Dublin City University.

Full text available as:

[img]
Preview
PDF (PhD thesis) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
4Mb

Abstract

Trastuzumab, a monoclonal antibody, and lapatinib, a tyrosine kinase inhibitor are approved treatments for HER2 positive breast cancer; however, patients that initially respond frequently develop resistance. The aims of this study were to investigate microRNA expression in acquired and/or innate trastuzumab and lapatinib resistant cell lines, and in a cohort of HER2 positive breast cancer patients. Four miRNAs were identified as altered in the acquired trastuzumab resistant cell lines;. miR-221, -222, -224 and -9. miR-221 and -224 are also involved in innate trastuzumab resistance. miR-221, -224, -30e-3p, -550, -92a and -9 are altered in acquired lapatinib resistant cells lines and miR-221 is associated with innate lapatinib resistance. These microRNAs are potential predictive biomarkers of innate and/or acquired resistance to HER2 targeted therapies. All-trans retinoic acid (ATRA) treatment alone or in combination with trastuzumab or lapatinib may overcome resistance in some HER2 positive breast tumours. Co-amplification of retinoic acid receptor alpha (RARα) with HER2 may be a potential biomarker to predict benefit from combined ATRA and HER2 targeted therapies. Over-expression of miR-221 and -222 in the SKBR3-P cell line does not confer resistance to trastuzumab. However, they increase the migratory potential of the SKBR3-P cell line. We identified miR-221, -222 and -9 expression is higher and miR-224 is lower in patients who did not achieve a durable complete response (non-DCR) compared to the DCR cohort. This miRNA profile may be predictive for acquired trastuzumab resistance. This is the f his is the f his is the f his is the first report of the involvement of miR-222, -224 and miR-9 in innate and acquired trastuzumab and/or lapatinib resistance in HER2 positive breast cancer. These miRNAs represent potential biomarkers of resistance and ATRA treatment may be a potential therapeutic strategy to overcome resistance, in some cases.

Item Type:Thesis (PhD)
Date of Award:November 2015
Refereed:No
Supervisor(s):O'Donovan, Norma and Crown, John
Uncontrolled Keywords:HER2; miRNA; Trastuzumab; Lapatinib
Subjects:Biological Sciences > Biology
Biological Sciences > Cell biology
Biological Sciences > Molecular biology
DCU Faculties and Centres:Research Initiatives and Centres > National Institute for Cellular Biotechnology (NICB)
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
Funders:Science Foundation Ireland, Cancer Clinical Research Trust
ID Code:20779
Deposited On:20 Nov 2015 14:43 by Norma O'Donovan. Last Modified 07 Sep 2016 01:02

Download statistics

Archive Staff Only: edit this record