Therapeutic potential of histone deacetylase inhibitors for breast cancer

Author(s): Srividya Viswanathan, Sarah Carothers, Bhuvaneswari Ramaswamy

Carcinogenesis is a complex interplay of genetic and epigenetic aberrations which lead to altered gene expression. Efforts to reverse these changes, in order to prevent and treat cancer, have been ongoing for several decades. Histone acetylation is one of the key epigenetic mechanisms involved in altering configuration of the chromatin structure, and is modulated by the opposing activities of histone acetyl-transferases and histone deacetylases. Histones whose lysine residues are heavily acetylated yield a more open chromatin structure, due to the repulsion of the negatively charged DNA strand by negatively charged acetylated lysine residues leading to transcriptional activation. Alternatively, histone deacetylation leads to gene repression, due to transcriptionally silent heterochromatin. Aberrant activity of histone acetyl-transferases and histone deacetylases leading to repression and activation of key genes has been documented in several cancers, including breast cancer. Hence, these enzymes are rational targets in cancer therapy to modulate gene expression, in particular genes involved in proliferation and differentiation. Novel histone deacetylase inhibitors have been developed, and preclinical and clinical data demonstrate their role in treatment and prevention of breast cancer. We present here the rationale for targeting histone deacetylases in breast cancer, and the preclinical and clinical data that support further development of these agents.