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BioAssay: AID 651736

qHTS Assay for Inhibitors of the Six1/Eya2 Interaction

The Six1 homeobox gene encodes a transcription factor that is crucial for the development of many organs but is down-regulated after organ development is complete. Its expression is low or undetectable in normal adult breast tissue but the gene is over-expressed in 50% of primary breast tumors and 90% of metastatic lesions. Our analysis of public microarray databases containing 535 breast cancer more ..
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AID: 651736
Data Source: NCGC (Six1000)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2012-10-31
Target
Depositor Specified Assays
AIDNameTypeComment
651725qHTS Assay for Inhibitors of the Six1/Eya2 Interactionscreening
Description:
The Six1 homeobox gene encodes a transcription factor that is crucial for the development of many organs but is down-regulated after organ development is complete. Its expression is low or undetectable in normal adult breast tissue but the gene is over-expressed in 50% of primary breast tumors and 90% of metastatic lesions. Our analysis of public microarray databases containing 535 breast cancer samples demonstrates that Six1 levels correlate significantly with shortened time to relapse, shortened time to metastasis, and decreased survival. Using transgenic and xenograft mouse models, we have demonstrated that mammary specific overexpression of Six1 results in enhanced proliferation, transformation, increased tumor volume, and metastasis. Importantly, RNA interference against Six1 significantly decreases breast cancer associated metastasis. Together these data demonstrate that Six1 is necessary and sufficient to induce breast cancer metastasis. Six1 does not have an intrinsic activation or repression domain and requires the Eya coactivator proteins to activate transcription. Similar to Six1, Eya2 is also not expressed in most normal adult tissues, but is reexpressed in cancers. The Six1-Eya interaction is essential for proliferation during embryonic development, and both Six1 and Eya2 have been independently implicated in the same types of cancer. Because Six1 and Eya2 are embryonic genes with little expression in adult tissues, inhibitors of their expression/activity are likely to have limited side effects. Our goal is to identify inhibitors of the Six1/Eya interaction for potential cancer therapy.

To this end, we have developed a homogenous AlphaScreen assay targeting the Six1/Eya interaction. We performed a large scale HTS of the Molecular Libraries Small Molecule Repository (MLSMR) to identify inhibitors of the Six1/Eya interaction as potential anti-cancer therapeutics. Compounds identified can also be used as chemical probes to better understand the biological functions of Six1 and Eya.

NIH Chemical Genomics Center [NCGC]
NIH Molecular Libraries Probe Centers Network [MLPCN]

MLPCN Grant: DA033147
Assay Submitter (PI): Rui Zhao, University of Colorado Denver
Protocol
Please see linked AIDs for detailed protocols.
Comment
This project is on-going and will be updated at a later point.
Additional Information
Grant Number: DA033147

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