The role of mediator complex in tamoxifen resistance of ER-positive breast cancer
Author(s)
Advisor
Çizmecioğlu, OnurDate
2022-01Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
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Abstract
Breast cancer is the most prevalent cancer type and the leading cause of cancer
mortality among women worldwide. Estrogen receptor-positive (ER+) breast cancer
is the most common clinical subtype with an incidence rate of approximately 80% of
all breast cancers. Tamoxifen is a highly effective hormonal therapy for ER-positive
breast cancer patients. However, its remarkable success is hampered by de novo or
acquired resistance. Despite several advances in therapy options for relapsing patients,
tamoxifen resistance is still an urgent clinical problem that needs to be addressed.
Therefore, there is a dire need for novel targeted therapies to confer tamoxifen
resistance in ER-positive breast cancer. The architecture of Mediator complex links
DNA-bound transcription factors to the general transcription machinery RNA
polymerase II. Mediator kinase module is dissociable part of the Mediator complex
and broadly involved in human cancers. However, the role of kinase module in
tamoxifen resistance has not been investigated. In this dissertation, I deciphered the association of Mediator kinase module in
tamoxifen resistance both in vitro and in vivo settings. Initially, our gene expression profiling and survival analyses revealed that Mediator subunit 13 (MED13) and
cyclin-dependent kinase 8 (CDK8) were significantly higher in tamoxifen-treated
patients, and this outcome strongly correlated with worsened patient survival. In vitro
inhibition of either MED13 via genetic modulation or CDK8 by highly selective
inhibitor, SNX631, significantly reversed tamoxifen resistance. Notably, targeting
MED13 or CDK8 resulted in inhibition of HER2/mTOR signaling and triggered
apoptosis. Mechanistically, we identified that inhibition of either MED13 or CDK8
combined with tamoxifen treatment reduced ErbB2 mRNA level. We further
demonstrated that CDK8 post-transcriptionally controls ErbB2 level via regulating
mRNA stability. Moreover, inducible silencing of MED13 in combination with
tamoxifen impaired the tumor growth. Similarly, in vivo treatment of SNX631
together with tamoxifen reduced tumor growth in xenografts and prolonged the lifespan
in an aggressive transgenic mouse model. These results provided insight into
how transcriptional programmers MED13 and CDK8, could contribute to mediating
tamoxifen resistance and added new dimension to treatment strategies for ER-positive
breast cancer.