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 ERalpha-positive and ERalpha-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 G(0)-G(1) phase of the cell cycle. These effects were accompanied by decreased Rb phosphorylation, hyperacetylation of the p21(WAF1/CIP1) gene promoter and increased p21 protein expression. Only in breast cancer cells, cyclin B1 expression was decreased and the cells accumulated also in G(2). ERalpha expression decreased in ERalpha-positive, increased in ERalpha-negative and was unchanged in normal mammary epithelial cells, as did the expression of progesterone receptor, a physiological ERalpha target. VPA decreased the expression of the invasiveness marker pS2 in ERalpha-positive breast cancer cells, but did not cause its re-expression in ERalpha-negative cells. Overall, these data suggest that in both ERalpha-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.
Travaglini
Lorena
L
Department of Histology & Medical Embryology, University of Rome La Sapienza, Italy.
Vian
Laura
L
Billi
Monia
M
Grignani
Francesco
F
Nervi
Clara
C
D000107:Acetylation; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000187:drug effects / Q000378:metabolism; D014635:Valproic Acid / Q000378:metabolism / Q000494:pharmacology*
D018797:Cell Cycle Proteins; D047628:Estrogen Receptor alpha; D006657:Histones; D014635:Valproic Acid