Related Experiment Video
Updated: Jun 26, 2025
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Targeting circadian transcriptional programs through a cis-regulatory mechanism in triple negative breast cancer
Abstract:
Circadian clock genes are emerging targets in many types of cancer, but their mechanistic contributions to tumor progression are still largely unknown. This makes it challenging to stratify patient populations and develop corresponding treatments. In this work, we show that in breast cancer, the disrupted expression of circadian genes has the potential to serve as biomarkers. We also show that the master circadian transcription factors (TFs) BMAL1 and CLOCK are required for the proliferation of metastatic mesenchymal stem-like (mMSL) triple-negative breast cancer (TNBC) cells. Using currently available small molecule modulators, we found that a stabilizer of cryptochrome 2 (CRY2), the direct repressor of BMAL1 and CLOCK transcriptional activity, synergizes with inhibitors of proteasome, which is required for BMAL1 and CLOCK function, to repress a transcriptional program comprising circadian cycling genes in mMSL TNBC cells. Omics analyses on drug-treated cells implied that this repression of transcription is mediated by the transcription factor binding sites (TFBSs) features in the cis-regulatory elements (CRE) of clock-controlled genes. Through a massive parallel reporter assay, we defined a set of CRE features that are potentially repressed by the specific drug combination. The identification of cis -element enrichment might serve as a new concept of defining and targeting tumor types through the modulation of cis -regulatory programs, and ultimately provide a new paradigm of therapy design for cancer types with unclear drivers like TNBC.
Insights
Disrupted circadian clock genes in breast cancer could be biomarkers. Targeting BMAL1/CLOCK with CRY2 stabilizers and proteasome inhibitors represses cancer cell proliferation.
Area of Science:
- Cancer Biology
- Chronobiology
- Genomics
Background:
- Circadian clock genes are implicated in cancer, but their roles in tumor progression are unclear.
- Disrupted circadian gene expression in breast cancer may serve as diagnostic biomarkers.
- Master circadian transcription factors BMAL1 and CLOCK are crucial for metastatic mesenchymal stem-like (mMSL) triple-negative breast cancer (TNBC) cell proliferation.
Purpose of the Study:
- To investigate the role of circadian clock genes in breast cancer progression.
- To identify potential therapeutic strategies targeting circadian pathways in TNBC.
- To explore the use of circadian gene expression as biomarkers for patient stratification.
Main Methods:
- Utilized small molecule modulators targeting cryptochrome 2 (CRY2) and proteasome inhibitors.
- Performed omics analyses on drug-treated mMSL TNBC cells.
- Employed massive parallel reporter assays to define cis-regulatory element (CRE) features.
Main Results:
- A combination of a CRY2 stabilizer and proteasome inhibitors repressed circadian cycling genes in mMSL TNBC cells.
- Omics data suggested that transcription factor binding sites (TFBSs) in CREs mediate this repression.
- Identified specific CRE features repressed by the drug combination.
Conclusions:
- Disrupted circadian gene expression in breast cancer holds potential as a biomarker.
- Targeting BMAL1 and CLOCK activity via CRY2 stabilizers and proteasome inhibitors shows therapeutic promise for TNBC.
- Modulating cis-regulatory programs offers a novel paradigm for designing therapies for cancers with undefined drivers, like TNBC.
Related Concept Videos
02:19Circadian Rhythms and Gene Regulation
02:02Cis-regulatory Sequences
01:37Epigenetic Regulation
X-chromosome...
02:23Master Transcription Regulators
01:23Negative Regulator Molecules
02:04Co-activators and Co-repressors