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Review
. 2022 Aug 30:13:977331.
doi: 10.3389/fendo.2022.977331. eCollection 2022.

Androgen receptor in breast cancer: The "5W" questions

Sara Ravaioli  1 , Roberta Maltoni  1 , Barbara Pasculli  2 , Paola Parrella  2 , Anna Maria Giudetti  3 , Daniele Vergara  3 , Maria Maddalena Tumedei  1 , Francesca Pirini  1 , Sara Bravaccini  1
Affiliations
Review

Androgen receptor in breast cancer: The "5W" questions

Sara Ravaioli et al. Front Endocrinol (Lausanne). .

Abstract

Androgen receptor (AR) is expressed in 60-70% of breast cancers (BCs) and the availability of anti-AR compounds, currently used for treating prostate cancer, paves the way to tackle specifically AR-positive BC patients. The prognostic and predictive role of AR in BC is a matter of debate, since the results from clinical trials are not striking, probably due to both technical and biological reasons. In this review, we aimed to highlight WHAT is AR, describing its structure and functions, WHAT to test and HOW to detect AR, WHERE AR should be tested (on primary tumor or metastasis) and WHY studying this fascinating hormone receptor, exploring and debating on its prognostic and predictive role. We considered AR and its ratio with other hormone receptors, analyzing also studies including patients with ductal carcinoma in situ and with early and advanced BC, as well. We also emphasized the effects that both other hormone receptors and the newly emerging androgen-inducible non coding RNAs may have on AR function in BC pathology and the putative implementation in the clinical setting. Moreover, we pointed out the latest results by clinical trials and we speculated about the use of anti-AR therapies in BC clinical practice.

Keywords: AR biomarker; AR signaling; AR/ER ratio; anti-AR therapy; breast cancer.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Functional domains of the androgen receptor: N-terminal domain (NTD), DNA binding domain (DBD), Ligand binding domain (LBD). (H – hinge region, AF-1 – transcriptional activating function 1, AF-2 – transcriptional activating function 2, NLS – nuclear localization signal, NES – nuclear export signal).
Figure 2
Figure 2
Genomic and non-genomic signaling of AR. Created with BioRender.com. In the absence of ligand, AR is located in the cytoplasm and is associated with heat-shock and other chaperone proteins. The binding of AR with androgens leads to the translocation of the complex to the nucleus, causes its dimerization and the binding to AREs, within classical target genes to modulate transcription. AR signaling exerts inhibitory effects on cell growth, interacting and binding to EREs and competing with ER. The DNA binding independent actions of AR are also commonly referred to in the literature as ‘non-genomic’ AR signaling with the downstream activation of alternative pathways, involving extracellular signal-regulated kinase (ERK), akt serine/threonine kinase (AKT) and mitogen- activated protein kinases (MAPK).
Figure 3
Figure 3
Analysis of AR status in the patient who had stable disease with DHEA: (A) AR copy number, evaluated by FISH, showing clusters of orange signals; (B) AR positive nuclear expression by IHC; (C) AR pSer210-213 positive but weak nuclear and cytoplasmic expression; (D) AR pSer650 positive nuclear expression.
See this image and copyright information in PMC

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