TWIST1 GENE EXPRESSION AS A BIOMARKER FOR
PREDICTING PRIMARY DOXORUBICIN RESISTANCE
IN BREAST CANCER
Demir S1,10,*, Müslümanoğlu MH2, Müslümanoğlu M3, Başaran S4,
Çalay ZZ5, Aydıner A6, Vogt U7, Çakır T8, Kadıoğlu H9, Artan S1
*Corresponding Author: Selma Demir, Ph.D., Trakya University Faculty of Medicine, Department of
Medical Genetics, 22030 Iskender, Edirne, Turkey. Tel: +90(284)2357642/2330. Fax: +90(284)2357652.
E-mail: selmaulusal@trakya.edu.tr
page: 25
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DISCUSSION
Chemotherapy resistance is one of the major obstacles
to successful treatment of breast cancer [18]. Determination
of clinical/pathological complete response to adjuvant
chemotherapy takes time [19]. On the other hand,
the use of in vitro methods such as ATP-TCA for the rapid
determination of the response of cells to various agents,
give the opportunity to find and/or validate biomarkers
for predicting the response of tumors to chemo-therapeutics
and this is an important part of precision medicine
[20-22]. Culturing patient-derived tumor samples with
chemo-therapeutic agents planned to be used for a patient
and predicting the response rate via measuring ATP levels
at the end of the culture period takes about a week. In
this study, we showed that doxorubicin-resistant primary
breast tumor samples have a higher twist expression. This
finding supports the role of the twist transcription factor
as a predictive biomarker of doxorubicin chemotherapy.
As far as we know, there are no studies investigating the
direct association of TWIST gene expression differences
in primary breast tumors and their individual sensitivity
to doxorubicin simultaneously.
The first evidence that TWIST overexpression was
blocking the apoptosis had been reported in a study by
Maestro et al. [23], which they performed on rhabdomyosarcomas.
Subsequent studies indicating an association
between TWIST gene expression and chemo-resistance
are based on the cell lines. The blocking effect of TWIST
upregulation on cytotoxicity has been further supported
in a study performed on HtTA, HtTA-RelA, CCR3, PC3
cell lines. According to the evidences of this study, TWIST
overexpression was controlling both necrotic and apoptotic
pathways induced by cytotoxic agents. [24].
In cell line studies to investigate the drug resistance,
increased concentrations of drugs are used to make cells
resistant to the agents tested. This approach is due to the
fact that chemo-therapeutic agents also promote resistant
cell phenotypes. The first study indicating twist transcription
factor as a biomarker performed with taxol resistant
MCF-7 cell line, TWIST gene expression has been found
to play important roles in drug resistance [25]. In a study
conducted by Li et al. [26], based on the hypothesis that
TWIST transcription factor can be effective in doxorubicin
resistance, MCF7 cell lines were first rendered drug-resistant.
Adriamycin-induced resistance was shown to be
related to the more invasive potential and drug-resistant
phenotype of the cells. This resistant phenotype was mediated
by the epithelial-mesenchymal transformation process
in which the twist transcription factor plays a major
role [26]. Saxena et al. [27] reported that resistance to
chemotherapy and twist transcription factor expression
increased in invasive breast tumor cell lines exposed to
doxorubicin. In accordance with this study, Li et al. [26]
showed that TWIST1-mediated epithelial-mesenchymal
transition was responsible for multiple drug resistance and
twist depletion has enhanced the efficacy of doxorubicin
by partial suppression of drug-induced P-glycoprotein expression
in breast cancer cells. In our study, we found that
twist transcription factor expression differed before tumor
cells were exposed to any chemo-therapeutic agent, and
there was a significant relationship between breast tumor
response to doxorubicin and increased expression of the
twist transcription factor. Therefore, in accordance with
the other studies, the results of our study indicate that the
expression of induced or naturally increased TWIST1 gene
expression in breast tumors is associated with resistance
to chemotherapy.
Having compatible results with earlier cell line studies
on the role of twist overexpression as a biomarker for
doxorubicin chemo-resistance, this study also supports
effectivity of ATP-TCA assay method as a valuable tool
for biomarker prediction and validation studies. However,
drug-metabolizing reactions in the liver, tumor vascularization
[28], hypoxia levels [29] are some of the factors
that may affect the clinical drug response and may not be
precisely reflected during the in vitro chemo-sensitivity
assays. Together with these, the small sample number is
the restrictive property of this study. In conclusion, the
current study that has been performed with individual
primary breast tumor samples supports earlier studies that
have been performed with cell lines, suggesting the role
of TWIST gene expression as a candidate biomarker for
predicting the response of breast tumors to the chemotherapeutic
agent doxorubicin.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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