Suberoylanilide Hydroxamic Acid, an Inhibitor of Histone Deacetylase, Enhances Radiosensitivity and Suppresses Lung Metastasis in Breast Cancer In Vitro and In Vivo

• Published in: PloS one Vol. 8; no. 10; p. e76340
• Main Authors: Chiu, Hui-Wen, Yeh, Ya-Ling, Wang, Yi-Ching, Huang, Wei-Jan, Chen, Yi-An, Chiou, Yi-Shiou, Ho, Sheng-Yow, Lin, Pinpin, Wang, Ying-Jan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.10.2013; Public Library of Science (PLoS)
• Subjects: Acids; Analysis; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis - radiation effects; Autophagy; Autophagy - drug effects; Autophagy - radiation effects; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Breast Neoplasms - radiotherapy; Cancer; Cancer metastasis; Cancer therapies; Cancer treatment; Cell cycle; Cell death; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell Movement - radiation effects; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Combined Modality Therapy; Combined treatment; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; DNA Repair - drug effects; DNA Repair - radiation effects; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - radiation effects; Epidermal growth factor; Estrogen receptors; Estrogens; Female; Gelatinase B; Gene expression; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylases - metabolism; Humans; Hydroxamic acid; Hydroxamic Acids - pharmacology; Hydroxamic Acids - therapeutic use; In vivo methods and tests; Inhibition; Inhibitors; Ionizing radiation; Kinases; Lung cancer; Lung Neoplasms - secondary; Metastases; Metastasis; Mice; Neoplasm Invasiveness; Pancreatic cancer; Phagocytosis; Progesterone; Proteins; Radiation; Radiation Tolerance - drug effects; Radiosensitivity; Recurrence (Disease); Stress response; Survival Analysis; Tumors; Xenograft Model Antitumor Assays; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0076340

Triple-negative breast cancer (TNBC), defined by the absence of an estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, is associated with an early recurrence of disease and poor outcome. Furthermore, the majority of deaths in breast cancer patients are from metastases instead of from primary tumors. In this study, MCF-7 (an estrogen receptor-positive human breast cancer cell line), MDA-MB-231 (a human TNBC cell line) and 4T1 (a mouse TNBC cell line) were used to investigate the anti-cancer effects of ionizing radiation (IR) combined with suberoylanilide hydroxamic acid (SAHA, an inhibitor of histone deacetylase (HDAC)) and to determine the underlying mechanisms of these effects in vitro and in vivo. We also evaluated the ability of SAHA to inhibit the metastasis of 4T1 cells. We found that IR combined with SAHA showed increased therapeutic efficacy when compared with either treatment alone in MCF-7, MDA-MB-231 and 4T1 cells. Moreover, the combined treatment enhanced DNA damage through the inhibition of DNA repair proteins. The combined treatment was induced primarily through autophagy and ER stress. In an orthotopic breast cancer mouse model, the combination treatment showed a greater inhibition of tumor growth. In addition, SAHA inhibited the migration and invasion abilities of 4T1 cells and inhibited breast cancer cell migration by inhibiting the activity of MMP-9. In an in vivo experimental metastasis mouse model, SAHA significantly inhibited lung metastasis. SAHA not only enhances radiosensitivity but also suppresses lung metastasis in breast cancer. These novel findings suggest that SAHA alone or combined with IR could serve as a potential therapeutic strategy for breast cancer.