Histaminergic System as a Promising Target for Breast Cancer Treatment

Abstract

Breast cancer is a heterogeneous disease that remains the deadliest cancer for women worldwide, which highlights the need of new effective therapeutic approaches especially in hard-to-treat breast cancer subtypes. From cell lines to animal models and human clinical studies, there is overwhelming evidence supporting the key role of the histaminergic system in breast cancer development and spread and in the response to cancer therapies. In this chapter, after briefly summarizing the most relevant aspects of histamine metabolism and histamine receptors’ characteristics, we will address the latest evidence on the role of the histaminergic system in the complex breast cancer biology, with particular emphasis on the identification of potential molecular targets for breast cancer therapies. Later on, we will discuss the contradictory roles of histamine in regulating the phenotype and functions of different immune cells and cancer cells. This review further highlights the immunomodulatory role of histamine and histamine receptors in breast cancer with implications in cancer immunotherapy. In this line, immune cells and also cancer cells can produce and respond to histamine, which denotes the complexity of the histamine/histamine receptor axis modulation of the antitumor immunity. To date, checkpoint inhibitor immunotherapy has the potential to generate tumor-specific and durable responses, revolutionizing the management of breast cancer. However, improvements in terms of rational immunotherapy combinations should be made to overcome reduced clinical responses, the lack of predictive biomarkers, and counteract acquired therapy resistance. In this scenario, the histaminergic system provides a promising strategy for the potential therapeutic exploitation of new immunomodulatory drug targets.