Targeting Unique Ligand Binding Domain Structural Features Downregulates DKK1 in Y537S ESR1 Mutant Breast Cancer
K S Young1, G R Hancock1, E Fink1
1Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 50153.
Biorxiv : the Preprint Server for Biology
|June 10, 2024
Summary
New selective estrogen receptor modulators (SERMs) like T6I-29 show promise against endocrine-resistant breast cancer. This study reveals T6I-29 downregulates DKK1, a potential therapeutic target in estrogen receptor-positive (ER+) breast cancer.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Endocrine therapy resistance is a major challenge in estrogen receptor-positive (ER+) breast cancer treatment.
- Mutations in estrogen receptor alpha (ERα), such as Y537S, confer resistance to standard therapies and promote metastasis.
- Next-generation selective estrogen receptor modulators (SERMs) and degraders (SERDs) show efficacy but often have non-durable responses.
Purpose of the Study:
- To comprehensively evaluate the activities of the novel SERM, T6I-29, against breast cancer cells harboring the Y537S ERα mutation.
- To investigate the molecular mechanisms underlying T6I-29's anti-proliferative effects.
- To identify potential new therapeutic targets in endocrine-resistant ER+ breast cancer.
Main Methods:
- Utilized structural-biochemical assays, in vitro experiments, and in vivo models.
- Performed RNA sequencing to analyze gene expression changes in response to T6I-29 treatment.
- Measured DKK1 levels in plasma from breast cancer patients and healthy controls.
Main Results:
- T6I-29 demonstrated significant anti-proliferative activity in Y537S ERα breast cancer cells.
- T6I-29 treatment led to a neomorphic downregulation of DKK1, a glycoprotein with known oncogenic roles.
- DKK1 was found to be significantly enriched in the plasma of ER+ breast cancer patients compared to healthy individuals.
Conclusions:
- The novel SERM T6I-29 is effective against Y537S ERα-mutated breast cancer.
- DKK1 represents a potential therapeutic target and biomarker in endocrine-resistant ER+ breast cancer.
- This research highlights new therapeutic avenues for endocrine-resistant ER+ breast cancers using novel SERMs and SERDs.
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