Pharmacological Inhibition of CBP/p300 Blocks Estrogen Receptor Alpha (ERα) Function through Suppressing Enhancer...

Area of Science:

• Molecular Oncology
• Epigenetics
• Breast Cancer Therapeutics

Background:

• Estrogen receptor alpha (ER) drives ER-positive breast cancer (BC).
• ER antagonists are standard treatment, but resistance is common.
• CBP and p300 are key ER co-activators and potential drug targets.

Purpose of the Study:

• To investigate the efficacy of CBP/p300 inhibitors in suppressing ER signaling in ER+ BC.
• To elucidate the mechanism by which CBP/p300 inhibition affects ER target gene expression.

Main Methods:

• Treatment of ER+ BC cells with CBP/p300 inhibitors (A-485, GNE-049).
• Analysis of ER, c-Myc, and Cyclin D1 expression.
• Cell growth inhibition and senescence induction assays.
• Microarray, RNA-seq, and ChIP-seq analyses to assess gene expression and epigenetic modifications.

Main Results:

• CBP/p300 inhibitors downregulated ER, attenuated estrogen-induced c-Myc and Cyclin D1, and inhibited BC cell growth via senescence.
• Global inhibition of estrogen-regulated genes confirmed ER inhibition as an on-target effect.
• A-485 suppressed H3K27 acetylation in ER target gene enhancers, correlating with decreased gene expression.

Conclusions:

• CBP/p300 inhibitors effectively suppress ER signaling and inhibit ER+ BC cell growth.
• Inhibition of CBP/p300 acetyltransferase activity provides a mechanism for downregulating the ER gene network.
• CBP/p300 represent promising therapeutic targets for ER+ breast cancer treatment.