Oncogenic EP300 can be targeted with inhibitors of aldo-keto reductases

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• EP300 is down-regulated in aggressive metaplastic breast carcinoma.
• EP300's role in breast cancer progression is complex, with conflicting reports of tumor suppressor and oncogenic functions.
• E-cadherin expression is critical for epithelial cell adhesion and is often lost in invasive cancers.

Purpose of the Study:

• To investigate the regulatory role of EP300 in E-cadherin expression and its impact on breast cancer.
• To elucidate the dual role of EP300 in breast cancer based on E-cadherin promoter status.
• To identify EP300-regulated effectors involved in cancer stemness and drug resistance.

Main Methods:

• Immunohistochemistry analysis of EP300 and E-cadherin in 41 invasive breast cancer cases and 20 non-malignant tissues.
• Generation of a breast cancer cell model (HS578T) with hypermethylated E-cadherin promoter for EP300 overexpression studies.
• Genome-wide expression profiling to identify EP300-regulated genes.
• Pharmacological inhibition of identified targets (aldo-keto reductases) to assess functional impact.

Main Results:

• EP300 and E-cadherin expression positively correlated in non-malignant and cancer tissues.
• EP300 and E-cadherin together predicted lymph node metastasis better than E-cadherin alone, supporting a metastasis suppressor role.
• In cells with a permissive E-cadherin promoter, EP300 suppressed metastasis by up-regulating E-cadherin and maintaining epithelial phenotype.
• In cells with a hypermethylated E-cadherin promoter, EP300 overexpression increased mesenchymal and stemness markers, migration, invasion, and drug resistance.
• Aldo-keto reductases (AKR1C1-3) were identified as key mediators of EP300-induced stemness and drug resistance.
• Inhibition of aldo-keto reductases restored sensitivity to chemotherapy and reduced mammosphere formation.

Conclusions:

• EP300 functions as a tumor/metastasis suppressor in breast cancer cells with a permissive E-cadherin promoter by enhancing E-cadherin expression and epithelial phenotype.
• EP300 acts as an oncogene in breast cancer cells with a hypermethylated E-cadherin promoter, promoting stemness, invasion, and drug resistance via aldo-keto reductases.
• Targeting aldo-keto reductases with inhibitors presents a potential therapeutic strategy for breast cancer, particularly in cases where EP300 may promote oncogenesis.