Prognostic significance of androgen receptor expression in invasive breast cancer: transcriptomic and protein expression analysis

Aleskandarany, Mohammed A.; Abduljabbar, Rezvan; Ashankyty, Ibraheem; Elmouna, Ahmed; Jerjees, Dena; Ali, Simak; Buluwela, Laki; Diez-Rodriguez, Maria; Caldas, Carlos; Green, Andrew; Ellis, Ian O.; Rakha, Emad A.

doi:10.1007/s10549-016-3934-5

Cited by 88 publications

(95 citation statements)

References 53 publications

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“…AR was prognostic in this study for all breast cancer cases in both cohorts, which likely reflects its negative correlation with tumor size and proliferative capacity, regardless of ERa status as shown in this study and previously reported (3,5,55). A recent meta-analysis in which AR mRNA expression was correlated with various gene signatures in large combined breast cancer cohorts strongly supports this concept (26).…”

Section: Discussionsupporting

confidence: 83%

The Magnitude of Androgen Receptor Positivity in Breast Cancer Is Critical for Reliable Prediction of Disease Outcome

Ricciardelli

Bianco‐Miotto

Jindal

et al. 2018

Clinical Cancer Research

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Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival.Experimental Design: AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts [training cohort, n ¼ 219; validation cohort, n ¼ 418; 77% and 79% estrogen receptor alpha (ERa) positive, respectively]. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts.Results: AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48%) previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1% nor 10% cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41; P ¼ 0.015) and validation (HR, 0.50; P ¼ 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERa-positive tumors and AR positivity !78% had the best survival in both cohorts (P < 0.0001). Among the combined ERa-positive cases, those with comparable or higher levels of AR (AR:ERa-positivity ratio >0.87) had the best outcomes (P < 0.0001).Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer.

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Section: Discussionsupporting

confidence: 83%

The Magnitude of Androgen Receptor Positivity in Breast Cancer Is Critical for Reliable Prediction of Disease Outcome

Ricciardelli

Bianco‐Miotto

Jindal

et al. 2018

Clinical Cancer Research

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“…Our data were further supported by Jiang et al [15]. who showed that AR expression was associated with decreased DFS in TNBC, but were not in agreement with a recent study, which indicated that AR expression was associated with favorable prognosis such as smaller tumor size, lower grade, and overall survival, particularly in the luminal breast cancer subtypes [30]. Nevertheless, emerging evidence implied intratumoral heterogeneity as a considerable issue that might influence the suitability of core biopsy.…”

Section: Discussionsupporting

confidence: 65%

The Androgen Receptor Promotes Cellular Proliferation by Suppression of G-Protein Coupled Estrogen Receptor Signaling in Triple-Negative Breast Cancer

Shen

Yang

Zhang

et al. 2017

Cell Physiol Biochem

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Background/Aims: The targeted therapy for triple-negative breast cancer (TNBC) is still challenging due to poor understanding on its molecular etiology. The androgen receptor (AR) has recently emerged as a prognostic and treatment-predictive marker in breast cancer. However, the role of AR in TNBC remained elusive. Methods: Immunohistochemistry (IHC) was used to detect AR and G-protein coupled estrogen receptor (GPER) expression in tissue microarrays of 165 TNBC patients. Microarray analysis of mRNAs was performed to identify downstream regulators of AR. TNBC cells were cultured with dihydrotestosterone (DHT) alone or in combination with AR knockdown performed with AR shRNA. Cell viability and colony formation were assessed. Western blotting and qRT-PCR were used to examine protein and mRNA expression, respectively. The potential mechanism of AR-mediated GPER suppression was identified by Chromatin immunoprecipitation (ChIP) assay. AR and GPER expressions were also assessed in nude mouse xenografts by IHC. Results: IHC staining showed that the expression of AR was positively associated with tumor size, lymph node metastasis and high-grade tumor in TNBC patients. AR activation triggered by DHT suppressed GPER expression, to promote cell growth of TNBC. G-1, a GPER agonist, inhibited DHT-stimulated proliferation. Further experiments illustrated that AR suppressed GPER activation via binding directly to the promoter of GPER. Moreover, a negative correlation between AR and GPER was observed in MDA-MB-231 tumor cell xenografts and TNBC patient samples. Conclusions: The suppression of GPER via AR may be involved in the positive actions towards the TNBC progression, making it a promising therapeutic target for TNBC treatment.

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“…However, although showing a trend toward improvement, the difference in OS was not statistically significant [61]. Aleskandarany et al performed a retrospective cohort study of stage I-III patients ( n = 1141) with tumors ≤5 cm from 1987 to 1997 [62]. High AR expression was associated with longer breast cancer specific survival (BCSS) and was an independent predictor of better outcome regardless of tumor size, grade and nodal stage.…”

Section: Prognostic Implications Of Ar In Er+ Breast Cancermentioning

confidence: 99%

AR Signaling in Breast Cancer

Rahim

O’Regan

2017

Cancers

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Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies.

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Prognostic significance of androgen receptor expression in invasive breast cancer: transcriptomic and protein expression analysis

Abstract: Background: Differential prognostic roles of Androgen Receptor (AR) have been proposed

Cited by 88 publications

References 53 publications

The Magnitude of Androgen Receptor Positivity in Breast Cancer Is Critical for Reliable Prediction of Disease Outcome

The Magnitude of Androgen Receptor Positivity in Breast Cancer Is Critical for Reliable Prediction of Disease Outcome

The Androgen Receptor Promotes Cellular Proliferation by Suppression of G-Protein Coupled Estrogen Receptor Signaling in Triple-Negative Breast Cancer

AR Signaling in Breast Cancer

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