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

Abstract

E-cadherin transcriptional activator EP300 is down-regulated in metaplastic breast carcinoma, a rare form of triple negative and E-cadherin-negative aggressive breast cancer with a poor clinical outcome. In order to shed light on the regulation of Ecadherin by EP300 in breast cancer we analyzed by immunohistochemistry 41 cases of invasive breast cancer with both E-cadherin high and E-cadherin low expression levels, together with 20 non-malignant breast tissues. EP300 and E-cadherin showed a positive correlation in both non-malignant and cancer cases and both markers together were better predictors of lymph node metastasis than E-cadherin alone. These data support a metastasis suppressor role for EP300 in breast cancer. However, some reports suggest an oncogenic role for EP300. We generated a breast cancer cell model to study E-cadherin-independent effects of EP300 by over-expressing of EP300 in HS578T cells which have E-cadherin promoter hypermethylated. In this cell system, EP300 led to up-regulation of mesenchymal (vimentin, Snail, Slug, Zeb1) and stemness (ALDH + and CD44 high /CD24 low ) markers, increases in migration, invasion, anchorage-independent growth and drug resistance. Genome-wide expression profiling identified aldo-keto reductases AKR1C1-3 as effectors of stemness and drug resistance, since their pharmacological inhibition with flufenamic acid restored both doxorubicin and paclitaxel sensitivity and diminished mammosphere formation. Thus, in cells with a permissive E-cadherin promoter, EP300 acts as a tumour / metastasis supressor by up-regulating E-cadherin expression, maintenance of the epithelial phenotype and avoidance of an epithelial-to-mesenchymal transition. In cells in which the E-cadherin promoter is hypermethylated, EP300 functions as an oncogene via upregulation of aldo-keto reductases. This offers the rationale of using current aldo-keto reductase inhibitors in breast cancer treatment.3

EP300 Knockdown Reduces Cancer Stem Cell Phenotype, Tumor Growth and Metastasis in Triple Negative Breast Cancer

“…Based on our ndings, future studies should investigate whether EP300 targeted drugs ( ufenamic acid [18], VV59 [19], A-485 [41]) can inhibit tumor initiation and metastasis in TNBC pre-clinical models.…”

“…As part of various transcriptional complexes EP300 has important and diverse biological functions in cellular proliferation, cell cycle regulation, apoptosis, DNA damage repair, cell fate determination and stem cell pluripotency [14]. EP300 has been implicated in cancer biology in general [15] and breast cancer in particular [16], and has been described as both a tumor suppressor [16,17] and more recently as an oncogene promoting tumor growth, metastatic potential and CSC phenotype in BC [18]- [20]. In TNBC speci c EP300 mutations have been described and EP300 was included in the triple negative breast cancer team project biomarker panel [21].…”

EP300 Knockdown Reduces Cancer Stem Cell Phenotype, Tumor Growth and Metastasis in Triple Negative Breast Cancer

“…Based on our ndings, future studies should investigate whether EP300 targeted drugs ( ufenamic acid [18], VV59 [19], A-485 [41]) can inhibit tumor initiation and metastasis in TNBC pre-clinical models.…”

“…The role of the tumor microenvironment more generally seems to play a critical role in the ndings described here and invites further detailed experimentation. EP300 has been found to have tumor suppressor [16], [17] as well as an oncogenic properties [18], [19]. Another famous tumor suppressor, TP53, has been shown to potentially have pro-tumorigenic effects via increased in ammation [52] or anti-apoptotic mechanisms [53].…”

“…As part of various transcriptional complexes EP300 has important and diverse biological functions in cellular proliferation, cell cycle regulation, apoptosis, DNA damage repair, cell fate determination and stem cell pluripotency [14]. EP300 has been implicated in cancer biology in general [15] and breast cancer in particular [16], and has been described as both a tumor suppressor [16,17] and more recently as an oncogene promoting tumor growth, metastatic potential and CSC phenotype in BC [18]- [20]. In TNBC speci c EP300 mutations have been described and EP300 was included in the triple negative breast cancer team project biomarker panel [21].…”