Six1 is a developmental gene that is abnormally re-expressed in a large percentage of breast cancers. This over-expression plays a causal role in the initiation and metastatic development of breast cancers. Since Six1 does not have its own activation or repression domain, the Eya family of Six1 co-activator proteins is essential for Six1-mediated breast tumorigenesis and metastasis. We have developed an AlphaScreen based HTS assay targeting the Six1/Eya interaction. We propose to perform a large scale high throughput screening using the NIH MLPCN compounds to identify inhibitors of the Six1/Eya interaction. We plan to test these inhibitors for their potential as therapeutic tools to inhibit Six1-mediated breast tumorigenesis and metastasis. These inhibitors can also be used as valuable chemical probes for studies involving the Six1/Eya interaction.

Public Health Relevance

Six1 is a transcription factor that is critical for the onset and progression of a large percentage of breast tumors, as well as for metastasis of hepatocellular carcinoma and rhabdomyosarcoma. Eya2 is a co-activator of Six1 that is essential for Six1-mediated tumorigenesis and metastasis. This project intends to identify small molecule inhibitors of the Six1/Eya interaction using high throughput screening for anti-cancer therapy. Because Six1 is overexpressed in 50% of primary breast tumors and 90% of metastatic lesions, we expect this work to potentially benefit a large population of breast cancer patients, as well as patients that harbor other types of tumors that overexpress Six1 and/or Eya.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
5R03DA033174-02
Application #
8296485
Study Section
Special Emphasis Panel (ZRG1-BST-F (50))
Program Officer
Purohit, Vishnudutt
Project Start
2011-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$37,840
Indirect Cost
$12,840
Name
University of Colorado Denver
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Zhou, Hengbo; Zhang, Lingdi; Vartuli, Rebecca L et al. (2018) The Eya phosphatase: Its unique role in cancer. Int J Biochem Cell Biol 96:165-170
Blevins, Melanie A; Towers, Christina G; Patrick, Aaron N et al. (2015) The SIX1-EYA transcriptional complex as a therapeutic target in cancer. Expert Opin Ther Targets 19:213-25
Patrick, Aaron N; Cabrera, Joshua H; Smith, Anna L et al. (2013) Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome. Nat Struct Mol Biol 20:447-53