Journal Article

Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer

Hirose, Makiko, Saji, Shigehira, Horiguchi, Shin-ichiro, Schreiber, Stuart L, Kawakami, Masayo, Funata, Nobuaki, Toi, Masakazu, Itoh, Akihiro, Yoshida, Nobuyuki, Hayashi, Shin-ichi, Yoshida, Minoru

2005

Overview

Histone deacetylase (HDAC) 6 is a subtype of the HDAC family; it deacetylates α -tubulin and increases cell motility. Here, we investigate the impact of an alteration of HDAC6 expression in estrogen receptor α (ER)-positive breast cancer MCF-7 cells, as we identified that HDAC6 is a novel estrogen-regulated gene. MCF-7 treated with estradiol showed increased expression of HDAC6 mRNA and protein and a four-fold increase in cell motility in a migration assay. Cell motility was increased to the same degree by stably transfecting the HDAC6 expression vector into MCF-7 cells. In both cases, the cells changed in appearance from their original round shape to an axon-extended shape, like a neuronal cell. This HDAC6 accumulation caused the deacetylation of α -tubulin. Either the selective estrogen receptor modulator tamoxifen (TAM) or the pure antiestrogen ICI 182,780 prevented estradiol-induced HDAC6 accumulation and deacetylation of α -tubulin, leading to reduced cell motility. Tubacin, an inhibitory molecule that binds to the tubulin deacetylation domain of HDAC6, also prevented estradiol-stimulated cell migration. Finally, we evaluated HDAC6 protein expression in 139 consecutively archived human breast cancer tissues by immunohistochemical staining. The prognostic analyses for these patients revealed no significant differences based on HDAC6 expression. However, subset analysis of ER-positive patients who received adjuvant treatment with TAM ( n =67) showed a statistically significant difference in relapse-free survival and overall survival in favor of the HDAC6-positive group ( P <0.02 and P <0.05, respectively). HDAC6 expression was an independent prognostic indicator by multivariate analysis (odds ratio=2.82, P =0.047). These results indicate the biological significance of HDAC6 regulation via estrogen signaling.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: 17β-Estradiol / Anilides - pharmacology / Antiestrogens / Apoptosis / Biological and medical sciences / Biology / Breast cancer / Breast Neoplasms - diagnosis / Breast Neoplasms - drug therapy / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cell adhesion & migration / Cell Biology / Cell Line, Tumor / Cell migration / Cell Movement / Cell physiology / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Cell Transformation, Neoplastic / Clinical trials / Deacetylation / Endocrine therapy / Estradiol - analogs & derivatives / Estradiol - pharmacology / Estrogen Antagonists - pharmacology / Estrogen Receptor alpha - drug effects / Estrogen Receptor alpha - metabolism / Estrogen receptors / Estrogens / Estrogens - metabolism / Female / Fundamental and applied biological sciences. Psychology / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Genes / Histone deacetylase / Histone Deacetylase 6 / Histone Deacetylase Inhibitors / Histone Deacetylases - drug effects / Histone Deacetylases - genetics / Histone Deacetylases - metabolism / Hospitals / Human Genetics / Humans / Hydroxamic Acids - pharmacology / Internal Medicine / Medical prognosis / Medicine / Medicine & Public Health / Molecular and cellular biology / Motility / mRNA / Multivariate Analysis / Oncology / original-paper / Patients / Prognosis / Protein folding / Proteins / Selective Estrogen Receptor Modulators - pharmacology / Statistical analysis / Tamoxifen - pharmacology / Tubulin / Tubulin - metabolism