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External control of Her2 expression and cancer cell growth by targeting a Ras-linked coactivator
Shinichi Asada1, Yongmun Choi, Masaki Yamada
1The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
Overproduction of the Her2 oncoprotein has been found in approximately 30% of breast tumors, and patients who have Her2 excesses typically have more aggressive disease. Here we show that the expression of the Her2 gene can be decreased by inhibiting the interaction of the two cancer-linked proteins, DRIP130/CRSP130/Sur-2 (a Ras-linked subunit of human mediator complexes) and ESX (an epithelial-restricted transcription factor). Disruption of the interaction by a short cell-permeable peptide reduced the expression of the Her2 gene and specifically impaired the growth and viability of Her2-overexpressing breast cancer cells. The association of ESX with DRIP130 is mediated by a small hydrophobic face of an 8-aa helix in ESX, suggesting a therapeutic approach to incapacitating the Her2 gene by small organic molecules.
Insights
Researchers found a way to reduce Her2 oncoprotein in breast cancer cells. Inhibiting the interaction between DRIP130 and ESX proteins decreased Her2 gene expression, impairing cancer cell growth.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Her2 oncoprotein overexpression is common in breast tumors, correlating with aggressive disease.
- Targeting Her2 is a key strategy in breast cancer treatment.
Purpose of the Study:
- To investigate a novel therapeutic strategy for Her2-overexpressing breast cancer.
- To identify molecular targets that regulate Her2 gene expression.
Main Methods:
- Utilized a short cell-permeable peptide to disrupt protein interactions.
- Assessed the impact of peptide treatment on Her2 gene expression.
- Evaluated the effects on breast cancer cell growth and viability.
Main Results:
- Inhibition of the DRIP130/CRSP130/Sur-2 and ESX protein interaction reduced Her2 gene expression.
- The peptide specifically impaired the growth and viability of Her2-overexpressing breast cancer cells.
- Identified a critical 8-amino acid helix in ESX mediating the association with DRIP130.
Conclusions:
- Disrupting the DRIP130-ESX interaction offers a potential therapeutic approach for Her2-positive breast cancers.
- Small organic molecules targeting the ESX helix could be developed to inhibit the Her2 gene.
- This strategy specifically targets cancer cells overexpressing Her2.