Androgen Receptor in Breast Cancer-Clinical and Preclinical Research Insights

Abstract

The Androgen Receptor (AR) is emerging as an important factor in the pathogenesis of breast cancer (BC), which is the most common malignancy among females worldwide. The concordance of more than 70% of AR expression in primary and metastatic breast tumors implies that AR may be a new marker and a potential therapeutic target among AR-positive breast cancer patients. Biological insight into AR-positive breast cancer reveals that AR may cross-talk with several vital signaling pathways, including key molecules and receptors. AR exhibits different behavior depending on the breast cancer subtype. Preliminary clinical research using AR-targeted drugs, which have already been FDA-approved for prostate cancer (PC), has given promising results for AR-positive breast cancer patients. However, since the prognostic and predictive value of AR positivity remains uncertain, it is difficult to identify and stratify patients that would benefit from AR-targeted therapies. Herein, through a review of preclinical studies, clinical studies, and clinical trials, we summarize the biology of AR, its prognostic and predictive value, as well as its therapeutic implications by breast cancer molecular subtype.

Keywords: androgen receptor; androgens; antiandrogens; breast cancer; estrogen receptor; triple negative breast cancer.

Figure 1

Mechanisms of AR mediated gene transcription in different subtypes of breast cancer. In ER-α-negative/HER 2-positive breast cancer, the Wnt/β-catenin pathway is implicated and facilitates the transcriptional activity of AR promoting tumor growth. In TNBC, androgens seem to initiate second-messenger signaling cascades, which often results in a feedback loop, leading to the progression of the tumor. In the ER-positive, BC subtype, there is a dynamic relationship between ER and AR, where the two receptors can transcriptionally regulate each other through heterodimerization and binding to the same DNA sequence. Abbreviations: AR—androgen receptor; ARE—androgen receptor element; DHT—dihydrotestosterone; TF—transcription factor.

Figure 2

AR signaling pathway and targeted therapeutic strategies against AR. AR can regulate the proliferation, migration, and invasiveness in BC through genomic and/or nongenomic pathways. CYP17A1 is the enzyme that converts androgen precursors into DHEA, HSD3β1 catalyzes DHEA to AD, while AKR1C3 converts AD to testosterone; finally, testosterone is catalyzed to DHT by 5α-reductase. In the genomic way of AR activation, DHT binds and activates AR, which disassociates from heat shock proteins and forms dimers, which translocate to the nucleus, where gene transcription is modulated by binding to the androgen response elements of target genes. In the nongenomic way of AR activation, ERK-mediated AR signaling involves phosphoinositide 3-kinase (PI3K), Src proteins, and Ras GTPase. Abiraterone acetate selectively and irreversibly blocks CYP17A1 activity. Drugs: Seviteronel is a CYP17A1 inhibitor. Bicalutamide is a first-generation and Enzalutamide a second-generation AR antagonist that blocks androgens binding to AR. Enzalutamide also inhibits AR nuclear translocation and AR-mediated transcription. In the nongenomic way of AR activation, the use of AR antagonists/inhibitors of AR-activated proteins that disrupts the AR/src association could be a starting point to reduce BC cell proliferation. Abbreviations: AD—androstenedione; AKR1C3—aldo-keto reductase family 1 member C3; AP—androgen precursors; AR—androgen receptor; ARE—androgen receptor element; CYP17A1—cytochrome P450 c17; DHEA—dehydroepiandrosterone; DHT—dihydrotestosterone; HSP—heat shock protein; HSD3β1—human 3-beta-hydroxysteroid dehydroxynase/delta5-4 isomerase type 1; T—testosterone; TF—transcription factor.