Characterization of chemosensitivity profiles of breast cancer cell lınes, with and without stem cell like features = Kök-hücre özelliği olan ve olmayan meme kanseri hücre hatlarının ilaç hassasiyet profillerinin tanımlanması
Author(s)
Advisor
Date
2014Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
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Abstract
Breast cancer is the second most common cause of death worldwide from cancer due to
complications with its diagnosis and resistance to therapy. Recent studies have shown that
breast tumors when compared with other solid tumors also contain a subpopulation termed as
cancer stem cells (CSCs). CSCs are hard to kill due to their therapy resistant capacities. These
unharmed cells then result into relapse of tumor after treatment. Some established breast
cancer cell lines also behave in similar fashion to CSCs in overall manner thus termed as CSC
like cell lines. This study primarily focuses on characterizing CSC like cell lines from non CSC
like cell lines based upon their gene expression and prediction of drugs which can target these
groups separately. In this study two databases, Cancer Cell Line Encyclopedia (CCLE) and
Cancer Genome Project (CGP), were used which contain gene expression data and drugs
cytotoxicity data for most of the established cancer cell lines. Breast cancer cell lines gene
expression data was used to predict two gene lists which can separate breast cancer cell lines
into CSC like and non CSC like cell lines by in silico analysis. These gene lists were named as
Patentable and Non Patentable. Additionally four drugs were predicted which can target CSC
like group (Midostaurin and Elesclomol) and non CSC like group (Panobinostat and Lapatinib)
separately. Later these findings were validated in vitro. Non Patentable gene list could not be
validated due to low concordance with microarray data. On the other hand, Patentable gene list
was validated and was found concordant with microarray data. Out of four selected drugs,
Panobinostat and Lapatinib showed increased toxicity to non CSC like cell lines while only
Midostaurin showed toxicity to CSC like cell lines. To investigate further that cell lines were
grown in 3D cell culture conditions, to increase their stem cell like properties (stemness). But
only one cell line MDA-MB-157 which was found as CSC like, showed expected behavior.
Additionally this cell line increased resistance to Lapatinib and Panobinostat and became more
sensitive to Midostaurin. Correlation analysis showed some genes as potential biomarkers for
selected drugs. In conclusion, in this study various genes are proposed to differentiate CSC like cell lines from non CSC like cell lines. And Midostaurin can be potential drug to treat CSC like
cells while Lapatinib and Panobinostat showed increased activity against non CSC like cell
lines.
Keywords
Breast cancerCancer stem cells
Midostaurin
Elesclomol
Lapatinib
Panobinostat
Mammosphere
CCLE
CGP
qPCR
3D cell culture