Androgen Receptor Function and Targeted Therapeutics Across Breast Cancer Subtypes

Emily A. Kolyvas; Carlos Caldas; Kathleen Kelly; Saif S. Ahmad


Breast Cancer Res. 2022;24(79) 

In This Article

AR Prognostic Value by Subtype

Luminal Breast Cancer

PAM50 is a commonly used method of classifying intrinsic subtypes of BC using a minimal gene set.[26] Under the PAM50 classification, BC, which is both ER+ and PgR+, is subclassified as luminal A and B. The luminal A are low proliferating and luminal B are divided into HER2+ and HER2–. The majority of luminal BCs express AR by IHC, and this expression is associated with a favourable prognosis.[27,28] One meta-analysis shows that in early BC, AR is more likely to be co-expressed in ER+ over ER– tumours (74.8% vs. 31.8%, respectively).[29] AR may act through genomic signalling interference to reduce the proliferation of BC in the presence of oestrogen. One proposed mechanism for growth inhibition in the ER+ BC subtypes is by competitive binding of AR to the ER binding site on DNA.[30] A crosstalk between AR and ER has been proposed, and preclinical data suggest AR can antagonize ER signalling, dependent upon the relative levels of each hormone receptor.[31] Contrastingly, in BCs that do not express ER, AR is able to bind to oestrogen response elements (EREs) on the DNA and stimulate cell proliferation.[32] A large-scale clinical and gene expression meta-analysis from Bozovic-Spasojevic et al. confirmed the findings shown in previous studies where AR positivity conferred improved disease-free survival and overall survival in ER+ BC.[33] Further support for this observation was seen in a retrospective study where patients with tumours expressing both AR and ER had a better prognosis than those with either AR or ER positivity.[32] Additionally, the ratio of the hormone receptors has been suggested as being relevant for prognostic value, with high AR relative to ER proving to be predictive of hormone therapy resistance in early studies.[34] While several studies support the improved prognostic value of AR in ER+ BC, some propose the activation of signalling pathways that would lead to increased proliferation of BC cells. Steroid receptors including AR can have extranuclear functions involved in cell growth and survival. For instance, AR is able to activate cell proliferation through oestradiol stimulation of the formation of a complex between AR, ER and Src. This complex ultimately activates the PI3K/Akt and MAPK pathways.[35,36] Disruption of the interaction between AR/Src weakens the formation of this complex and can inhibit proliferation.[37,38] Similarly, EGF signalling was dependent on the formation of this complex, confirming that the AR/ER/Src association plays a role in cell cycle progression.[39] Further studies show that hormone therapy resistance occurs in ER+ models with AR overexpression through EGFR.[40]

HER2-enriched Breast Cancer

AR is expressed in about 60% of HER2+ BC by IHC.[4] In women with HER2+ BC, findings consistently report a worse prognosis with AR positivity.[41] The mechanism proposed for this unfavourable prognosis is through AR signalling mediated transcriptional induction of ligands involved in Wnt/β catenin and HER2 signalling pathways. AR stimulated WNT7B activation leads to nuclear localization of β catenin and subsequent interaction of β catenin with AR to increase HER3 expression.[42] Both Wnt and HER2 signalling pathways have the potential for positive feed-forward activation of AR activity, suggesting an androgen-independent activation of AR in these tumours. This has also been demonstrated in castrate-resistant prostate cancer (CRPC).[43]

The efficacy of treatment of HER2+ AR+ BC with enzalutamide and trastuzumab (HER2 mAb) is currently under investigation in a phase 2 clinical trial (NCT02091960). In contrast to these findings, however, a gene expression analysis has found that overall survival is in fact better for AR mRNA expression in HER2+ BC. These conflicting results could be attributed to there being only modest overlap between transcriptional and IHC profiles for AR.[33,44]

Triple-negative Breast Cancer (TNBC)

TNBC is defined as lacking expression of ER, PgR and HER2. This occurs in approximately 15–20% of BCs, but represents a disproportionate rate of mortality, as it is a more aggressive subtype.[45] Quadruple negative breast cancer (QNBC) is broadly TNBC that also does not express AR.[46] Patients with early TNBC suitable for surgery are frequently offered adjuvant chemotherapy, if deemed fit enough. However, these patients continue to have overall poorer survival and higher rates of distant metastasis following treatment.[47] Due to the lack of molecular targets, new therapeutics are needed for this subtype.

TNBC has recently been further categorized based on the gene expression profiles by the Lehmann molecular classification as follows: basal-like (BL1 and BL2), mesenchymal, mesenchymal stem-like, immunomodulatory, and luminal androgen receptor (LAR).[48] AR positivity is reported between 12 and 50% of TNBC.[4,44,49] The existence of an AR-expressing subtype of TNBC along with somatic mutations identified in AR-responsive genes in some sequencing has sparked interest in AR as a target for therapy of this aggressive type.[50,51] These Lehmann subtypes are shown to respond differently to therapies, with the LAR type being less proliferative and less sensitive to chemotherapy than the basal type.[52,53] Many studies have shown that AR expression in TNBC is associated with lower histologic grade and lower clinical stage.[54–56] Other groups have shown that a lack of AR expression increases the risk of recurrence and metastasis in TNBC.[57,58] A retrospective study found AR positivity in TNBC to be associated with improved disease-free survival, while another found LAR TNBC to have higher overall survival.[59,60] Another recent study stratified patients into distinct TNBC risk groups, finding LAR (AR+, EGFR−) patients to be in a lower-risk group with a better prognosis and likely to benefit most from antiandrogen therapy. Alternatively, AR− and EGFR+ represent the high-risk group that has a worse prognosis and is more likely to benefit from chemotherapy.[61] The prognostic value of AR in TNBC is still uncertain, with some reports suggesting a positive prognosis with AR expression and others reporting no effect. This is likely variable based on the molecular profile of the cancer as well as the clinical context (Reviewed in Bozovic-Spasojevic et al. meta-analysis).[33] Understanding the prognostic value of AR under these variable molecular and clinical contexts will be instrumental in using AR-targeting therapies for the treatment of BC.

Apocrine Breast Cancer

Apocrine BCs are not classified as a distinct subtype within the PAM50 classification and they make up only around 1% of all BCs.[76] Apocrine BCs are ER/PgR– and generally, but not always, HER2−. Because of this and their uncommonness, apocrine BCs are generally grouped with TNBCs despite having distinct morphology. These tumours are characterized by having apocrine cells with oeosinophilic and granular cytoplasm and a low nuclear–cytoplasmic ratio. Additionally, activation of the AR signalling pathway is a prominent feature in apocrine BC.[77] Apocrine BCs are ER/PgR– and therefore may be either HER2-enriched or, more frequently triple-negative. Importantly not all AR+ but ER/PgR– BCs are apocrine.

Triple-negative apocrine BC frequently carry actionable genomic alterations including alterations in PIK3CA and PTEN.[78] Approximately 80% of invasive apocrine tumours occur in postmenopausal women.[79] Due to its relatively low prevalence, it remains unclear whether the clinical features and outcomes of apocrine BC differ significantly from non-apocrine BC (either AR+ or AR–). Recently, an AR+ apocrine cell line model was shown to have an AR-dependent proliferative response to androgens and expression of genes that are normally expressed in ER+ luminal tumours.[44] Further work showed that in this model AR binds and regulates ER cis-regulatory elements through a FoxA1-dependent mechanism leading to the gene expression profile overlap with ER+ BC.[80] Apocrine BC's strong association with AR highlights their importance as a model to understand AR signalling in BC, and these tumours should be enriched for clinical trials investigating AR-targeted agents.