AR/ER Ratio Correlates with Expression of Proliferation Markers and with Distinct Subset of Breast Tumors

Abstract

The co-expression of androgen (AR) and estrogen (ER) receptors, in terms of higher AR/ER ratio, has been recently associated with poor outcome in ER-positive (ER+) breast cancer (BC) patients. The aim of this study was to analyze if the biological aggressiveness, underlined in ER+ BC tumors with higher AR/ER ratio, could be due to higher expression of genes related to cell proliferation. On a cohort of 47 ER+ BC patients, the AR/ER ratio was assessed by immunohistochemistry and by mRNA analysis. The expression level of five gene proliferation markers was defined through TaqMan®-qPCR assays. Results were validated using 979 BC cases obtained from gene expression public databases. ER+ BC tumors with ratios of AR/ER ≥ 2 have higher expression levels of cellular proliferation genes than tumors with ratios of AR/ER < 2, in both the 47 ER+ BC patients (P < 0.001) and in the validation cohort (P = 0.005). Moreover, BC cases with ratios of AR/ER ≥ 2 of the validation cohort were mainly assigned to luminal B and HER2-enriched molecular subtypes, typically characterized by higher proliferation and poorer prognosis. These data suggest that joint routine evaluation of AR and ER expression may identify a unique subset of tumors, which show higher levels of cellular proliferation and therefore a more aggressive behavior.

Obesity and Androgen Receptor Signaling: Associations and Potential Crosstalk in Breast Cancer Cells

“…In contrast, recent results from an additional clinical trial, indicate that in ER+ BCs a subset of women with both high levels of AR mRNA and low levels of ESR1 (ER) mRNA, may benefit from enzalutamide in combination with the AI exemestane [ 140 ]. This confirm our previous reports which indicate that high AR levels respect to ER levels may help to identify and treat a specific subgroup of ER+ patients (luminal BC) having tumors with unfavorable clinical and molecular characteristics [ 90 , 136 ].…”

“…Hence, high AR expression in obesity could play a positive role in BC progression when ER expression levels are low. Consistent with this idea, patients with basal-like BCs (ER− or low expression) are more likely to be obese, compared with underweight/normal patients [ 26 ], and tumors with high AR and low ER expression levels (AR/ER ratio ≥2) are associated with more aggressive BC molecular subtypes [ 90 , 136 ]. Together these results allow suggest that in obesity ER expression may decrease, opening the possibility that the increased androgen synthesis observed in this environment, results in specific overstimulation of AR signaling to maintain active pathways related to tumor progression and aggressiveness.…”

“…Therefore, most of BC research has focus on identifying the targets and roles of this steroid receptor and its main ligand E2. However, an extensive amount of evidence suggests that estrogens are not the only steroid molecules related to BC [ 86 , 87 , 88 ], and it has even been shown that hormonally regulated transcription is remarkably maintained in BC subsets with low levels of ER expression or in patients with ER− BC tumors [ 89 , 90 ]. These insights indicate the involvement in BC of additional steroid hormones and its receptors, such as the AR, which is widely expressed in normal breast epithelial cells.…”

“…In line with the positive effect of the AR on cell growth, it has been demonstrated that high AR and low ER protein expression levels (AR/ER ratio ≥2) are associated with unfavorable clinical features, tamoxifen resistance and poor survival in ER+ BCs [ 135 , 136 ]. Additionally, ER+ tumors with increased AR expression levels, are characterized by enhanced expression of cell proliferation markers and preferentially classified as luminal B or HER2-enriched tumors [ 90 ], which are recognized as more aggressive molecular subtypes.…”

RNA Based Approaches to Profile Oncogenic Pathways From Low Quantity Samples to Drive Precision Oncology Strategies

“…In breast cancer patients, the highest average AR pathway activity score was found in the HER2 subtype . The ratio between AR and ER IHC staining has been suggested to be informative as to the functional role of the AR pathway in breast cancer (Rangel et al, 2018(Rangel et al, , 2020. STP analysis enabled calculation of an AR over ER pathway activity ratio instead of the AR over ER protein expression ratio, revealing a relatively low ratio in luminal A/B and a high ratio in higher grade HER2 and basal breast cancer subtypes.…”