EP300 knockdown reduces cancer stem cell phenotype, tumor growth and metastasis in triple negative breast cancer

• Published in: BMC cancer Vol. 20; no. 1; p. 1076
• Main Authors: Ring, Alexander, Kaur, Pushpinder, Lang, Julie E
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 10.11.2020; BioMed Central; BMC
• Subjects: Animal models; Animals; Antibodies; Apoptosis; ATP-binding cassette super-family G member 2 (ABCG2)/breast Cancer resistance protein (BCRP); Basal-like BC; Binding proteins; Biomarkers, Tumor - metabolism; Breast cancer; Cancer cells; Cancer metastasis; Cancer stem cells (CSC); Care and treatment; Cell adhesion & migration; Cell culture; Cell Cycle; Cell Movement; Cell Proliferation; Chemotherapy; Complications and side effects; Cytotoxicity; E1A-Associated p300 Protein - antagonists & inhibitors; E1A-Associated p300 Protein - genetics; E1A-Associated p300 Protein - metabolism; E1A-associated protein p300 (EP300); Ethanol; FDA approval; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Genotype & phenotype; Health aspects; Humans; Lymphatic Metastasis; Metastases; Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Neoplastic Stem Cells - cytology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Phenotype; Phenotypes; Proteins; Risk factors; Stem cells; Suspension culture; Triple negative breast cancer; Triple negative breast cancer (TNBC); Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Triple Negative Breast Neoplasms - prevention & control; Tumor cells; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Xenografts; United States; Germany; Metastasis; Triple negative breast cancer (TNBC); E1A-associated protein p300 (EP300); Cancer stem cells (CSC); ATP-binding cassette super-family G member 2 (ABCG2)/breast Cancer resistance protein (BCRP); Basal-like BC
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-020-07573-y

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with basal features, lacking the expression of receptors targeted successfully in other breast cancer subtypes. Treatment response to adjuvant and neoadjuvant chemotherapy is often short-lived and metastatic spread occurs at higher rates than other subtypes within the first five years after diagnosis. TNBCs exhibit stem cell features and are enriched for cancer stem cell (CSC) populations. E1A Binding Protein P300 (EP300) is a large protein with multiple cellular functions, including as an effector in stem cell biology. We used a genetic knockdown (KD) model of EP300 in TNBC cell lines to investigate the effect on CSC phenotype, tumor growth and metastasis. Side population assay and tumorsphere suspension culture were used in vitro. Xenograft mouse models were used for in vivo studies. We performed in silico analysis of publicly available gene expression data sets to investigate CSC gene expression and molecular pathways as well as survival outcomes associated with EP300 expression in patients with TNBC and basal-like BC. EP300 KD abolished the CSC phenotype by reducing ABCG2 expression, side population cells and tumorsphere formation capacity in vitro as well as tumor formation in a xenograft mouse model in vivo. Metastatic capacity was markedly reduced in EP300 KD cells in vivo, with no detection of circulating tumor cells. TCGA data analysis demonstrated that genes positively correlated with EP300 expression in TNBC and basal-like BC were associated with CSC biology. Survival analysis demonstrated that EP300 expression predicts poor recurrence free survival in TNBC and basal BC. We report a novel oncogenic role for EP300 in driving CSC phenotype representing a potential target to address tumor initiation and metastatic spread in TNBC and basal-like BC. EP300 might serve as a prognostic marker and potential therapeutic target in TNBC.