Androgen receptor as a target for the treatment of hormone receptor-negative breast cancer: an unchartered territory

Abstract

Estrogen receptor-negative (ER-) and progesterone receptor-negative (PR-) breast cancers represent approximately 30% of all breast cancers and, in general, have a more aggressive clinical course. They are unresponsive to antiestrogens, more likely to be poorly differentiated, of higher histological grade and are associated with a higher recurrence rate and decreased overall survival. Androgen receptor (AR) expression has been reported in over 70% of breast cancer and in 45–50% of patients with ER-negative breast cancer. There is emerging evidence that the androgen signaling pathway plays a critical role in breast carcinogenesis, independent of ER. Preclinical data have suggested the inhibitory role of adrenal steroids, such as dehydroepiandosterone (DHEA) and its sulfate on the growth of human ER-negative breast cancer cell lines, when these demonstrate a strong expression of AR. This potentially results in decreased AR gene expression. However, DHEA has been shown to stimulate growth in breast cancer cells when an ER is expressed in ER-positive breast cancer cells. Therefore, the effect of adrenal steroids may differ based on the tumor hormone receptor status and ER-/PR- breast tumors may not be truly hormone ‘insensitive’. Exploration of new androgen-based hormonal therapy is warranted in this patient population. This article reviews the role of the AR in breast cancer and discusses potential avenues for the treatment of ER-/PR-/AR+ tumors with ‘hormonal therapy’.