Project Details
Description
Targeted therapies have benefited survival from various cancers, including breast cancer. A
critical challenge of targeted therapies is the development of drug resistance and recurrence.
Thus, identification of mechanisms underlying the activation of compensatory pathways and
further development of new agents that synergize the targeted therapies are urgently needed.
This proposal seeks to determine the impact of KLF4 (Krüppel-like factor 4) proteolysis that
orchestrates the signaling initiated by estrogen or TGF-β in breast tumor initiation/invasion, as
well as resistance to endocrine therapy. Recent studies by us and others have revealed KLF4
to be a novel player that regulates estrogen receptor signaling as well as TGF-β signaling
pathways, and whose deregulation leads to tumorigenesis and drug resistance. We demonstrated that in response to estrogen, upregulation of KLF4 due to the suppression of
KLF4 turnover governed by the E3 ligase VHL/VBC facilitates estrogen-induced mitogenic
growth. We also observed in tamoxifen-resistant breast cancer cells that the accumulated
KLF4 due to the inhibition of KLF4 degradation because of the compensatory activation of
oncogenic TGF-β signaling attenuates the tamoxifen response. We further observed that while
β-TRCP/SCF mediates estrogen response through the elevation of KLF4 levels by destruction
of its E3 ligase VHL, TGF-β-activated Src induces accumulation of KLF4 via promoting the
degradation of VHL, which in turn antagonizes the tamoxifen response. The objective of this
project is to determine the mechanism by which the ubiquitin-proteasome system regulates
estrogen-induced KLF4 accumulation that ensures estrogen response, and by which the
activation of Src by compensatory TGF-β counteracts the tamoxifen response through
suppression of VHL-mediated KLF4 degradation. The ultimate goal of this application is to
identify the clinical relevance of KLF4 proteolytic regulation in breast tumor initiation/invasion
and anti-estrogen resistance, and further validate the therapeutic intervention of our newly
developed KLF4 inhibitor in the rescue of tamoxifen resistance. Our Specific Aims are the
following: (1) to determine how the ubiquitin degradation machinery orchestrates estrogeninduced KLF4 accumulation; (2) to determine how dysregulation of the KLF4-VHL/VBC axis leads to enhanced self-renewal of cancer stem cell, breast tumor initiation/progression, and
contributes to anti-estrogen resistance; and (3) to determine the impact of deregulation of the
KLF4-VHL/VBC axis in breast tumor initiation/invasion, and to validate the therapeutic
intervention of KLF4 inhibitor in the rescue of anti-estrogen resistance using murine models.
Status | Finished |
---|---|
Effective start/end date | 5/1/18 → 1/31/22 |
Funding
- National Cancer Institute (5R01CA202948-06)
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