Valproic acid as an adjunctive therapeutic agent for the treatment of breast cancer

Breast cancer is one of the leading causes of cancer-related death among women. A significant challenge in treating breast cancer is the limited array of therapeutic options and the rapid development of resistance to existing agents. Indeed, breast cancer patients, particularly those with hormone-receptor (HR)-positive breast cancer, initially respond to systemic treatment with cytotoxic, hormonal, and immunotherapeutic agents but frequently progress to a more advanced disease that is refractory to therapy. Thus, new agents are needed to improve the effectiveness of current agents, decrease the emergence of resistance, and increase disease-free survival. To this end, numerous agents have been investigated for use in combination with existing therapies. Histone deacetylase (HDAC) inhibitors are a class of potent epigenetic modulators that have been investigated recently for their potential use in the treatment of breast cancer. In this review, we will discuss the underlying molecular rationale for using HDAC inhibitors for the treatment of breast cancer. In particular, we will focus our discussion on the FDA approved HDAC inhibitor valproic acid (VPA) which has been shown to alter proliferation, survival, cell migration, and hormone receptor expression of breast cancer cells in both the pre-clinical and clinical settings. We also discuss the promising pre-clinical data suggesting that VPA can be repurposed as an adjunctive agent in combination with many cytotoxic, hormonal, and immunotherapeutic agents for the treatment of breast cancer. Finally, we will examine the current models used to study the actions of VPA on breast cancer alone and in tandem with other agents.