Epigenetic reprogramming of breast cancer cells by valproic acid occurs regardless of estrogen receptor status

Estrogen receptors (ERs) are a recognized prognostic factor and therapeutic target in breast cancer. The loss of ER expression relates to poor prognosis, poor clinical outcome and impairs the use of anti-estrogenic treatment. Histone deacetylase inhibitors are candidate drugs for cancer therapy. Among them, valproic acid (VPA) is a long used and safe anti-epileptic drug. We studied the biological consequences of the chromatin remodeling action of VPA in a normal human mammary epithelial cell line and in ERα-positive and ERα-negative breast cancer cell lines. In these cells and regardless of their ER status, VPA-induced cell differentiation, as shown by increased milk lipids production, decreased expression of the CD44 antigen and growth arrest in the G0–G1 phase of the cell cycle. These effects were accompanied by decreased Rb phosphorylation, hyperacetylation of the p21WAF1/CIP1 gene promoter and increased p21 protein expression. Only in breast cancer cells, cyclin B1 expression was decreased and the cells accumulated also in G2. ERα expression decreased in ERα-positive, increased in ERα-negative and was unchanged in normal mammary epithelial cells, as did the expression of progesterone receptor, a physiological ERα target. VPA decreased the expression of the invasiveness marker pS2 in ERα-positive breast cancer cells, but did not cause its re-expression in ERα-negative cells. Overall, these data suggest that in both ERα-positive and -negative malignant mammary epithelial cells VPA reprograms the cells to a more differentiated and “physiologic” phenotype that may improve the sensitivity to endocrine therapy and/or chemotherapy in breast cancer patients.