Inhibition of breast cancer progression by a novel histone deacetylase inhibitor, LW479, by down-regulating EGFR expression.

Abstract

Compounds targeting epigenetic events of tumours are likely to be an important addition to anticancer therapy. Histone deacetylase inhibitors (HDACI) have emerged as a promising novel class for therapeutic interventions associated with cancer, and many of them are currently in clinical investigation. Here, we assessed a novel hydroxamate-based HDACI, LW479, in breast cancer progression and explored its underlying mechanism(s). LW479 was identified using the HDACI screening kit. Western blot and flow cytometry were used to analyse the biological effects of LW479 as a novel HDACI. The effects of LW479 were assessed in mouse models of spontaneous and experimental breast cancer. Co-immunoprecipitation, immunofluorescent staining and chromatin immunoprecipitation assays along with immunohistochemical analysis, were used to elucidate the molecular basis of the actions of LW479. LW479 was identified as a novel HDACI and showed marked cytotoxicity and induced apoptosis, as well as cell cycle arrest, in a panel of breast cancer cell lines. Intraperitoneal injections of LW479 markedly suppressed breast tumour growth and pulmonary metastasis in nude mice. LW479 also decreased levels of EGF receptors (EGFR) by blocking the binding of the transcription factor Sp1 and HDAC1 to the EGFR promoter region. Our data have elucidated the mechanisms underlying the inhibition by LW479 of tumour growth and metastasis, in models of breast cancer with aberrant EGFR expression. LW479 could be a candidate drug for breast cancer prevention.