The clinical significance of androgen receptors in breast cancer and their relation to histological and cell biological parameters

Kuenen‐Boumeester, Vibeke; Kwast, Theodorus H. van der; Claassen, C.C.; Look, Maxime P.; Liem, G.S.; Klijn, J.G.M.; Henzen‐Logmans, S. C.

doi:10.1016/0959-8049(96)00112-8

Cited by 129 publications

(103 citation statements)

References 22 publications

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“…18,19,29,30,32,36,37 However, our study could not demonstrate significant association of androgen receptor with age, tumor size, lymph node status or basal-like phenotype. Its frequency of expression in our series is comparable with results of Collins et al, 38 and raises the possibility of targeted therapy to androgen receptor expressing tumors.…”

Section: Discussioncontrasting

confidence: 77%

“…In these studies, its expression by immunohistochemistry was shown to be associated with a good prognosis in ER/PRnegative cancers. 23 Conversely, loss of androgen receptor was associated with a poor prognosis in lymph node-positive ER/PR/Her2-negative breast cancers. 24 These findings are consistent with cellbased assays, where androgen receptor activation with the agonist 5-dihydrotestosterone 25 or dehydroepiandrosterone sulfate 26 inhibits cell growth in androgen receptor-positive breast cancer cell lines, suggesting initiation of a growth inhibitory signal in 27 have found that androgen receptor function can be inhibited by low doses of progestins, which are similar to doses achieved in the serum of women on hormone replacement therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have found that androgen receptor is expressed in 60-70% of breast cancers, regardless of ER status. 18,29,32 It was postulated by Doane et al 15 that androgen receptor functions as an antiproliferative effector in ER-positive breast cancer by antagonizing ER, whereas it facilitates tumor cell growth in an androgen-dependent manner in an ER-negative/androgen receptor-positive breast cancer cell line model.…”

Section: Discussionmentioning

confidence: 99%

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Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer

et al. 2014

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Treatment of triple-negative invasive breast cancers, defined by the absence of estrogen and progesterone receptors and c-erbB2 expression, remains challenging. Androgen receptor, a member of the nuclear receptor superfamily that is involved in signaling pathways regulating cell proliferation, has been implicated in breast tumorigenesis. We immunohistochemically examined the expression of androgen receptor, basal markers (CK14, 34bE12) and EGFR in 699 triple-negative invasive breast cancers in tissue microarrays using the streptavidin-biotin method, and correlated the findings with clinical outcome. Positive androgen receptor expression was defined as staining of 1% or more of tumor cell nuclei. Survival outcomes were estimated with the Kaplan-Meier method and compared between groups with log-rank statistics. Cox proportional hazards models were used to determine the effect of androgen receptor on survival outcomes. Immunohistochemical positivity was observed in 38% of tumors, with the proportion of stained tumor cells ranging from 1 to 95% (mean 29%, median 10%). Androgen receptor expression was inversely associated with histologic grade and mitotic score. CK14, 34bE12 and EGFR confirmed 85% of cases to be basal-like, without significant association of basal-like phenotype with androgen receptor expression. Disease-free survival was significantly better in androgen receptor-positive triple-negative breast cancer, with a trend for improved overall survival. Decreased recurrence likelihood in both triple-negative and basal-like tumors (hazard ratio, 0.704; 95% confidence intervals, 0.498-0.994; P ¼ 0.0464; and hazard ratio, 0.675; 95% confidence intervals, 0.468-0.974; P ¼ 0.0355, respectively) was noted within 5 years of diagnosis but not thereafter. Our study suggests that loss of androgen receptor in triple-negative breast cancers augurs a worse prognosis, including those with basal-like features. More work in elucidating its relationship with mechanisms of progression, as well as trials of targeted treatment for androgen receptor-expressing triple-negative tumors, needs to be performed.

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Section: Discussioncontrasting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer

et al. 2014

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“…AR expression has been found in 84% (47) to 91% (48) of clinical breast cancers, and associated with ER status, but has also been found in 49% of ER-negative tumors (49). Patients with tumors that coexpress AR with ER and progesterone receptor have shown longer disease-free survival (DFS) than patients whose tumors were negative for all three receptors (48), but AR protein levels have also served as an independent predictor of axillary metastases in multivariate analysis (47) Furthermore, AR expression has correlated with decreased histopathologic grade, greater age, and postmenopausal status, but also lymph node -positive status (50). In AR-positive/ER-negative tumors, AR expression again associated with positive and negative indicators/outcome such as increased age, postmenopausal status, and longer DFS but also tumor grade, tumor size, and HER-2/neu overexpression (49).…”

Section: Discussionmentioning

confidence: 99%

Exemestane's 17-hydroxylated metabolite exerts biological effects as an androgen

Ariazi

Leitão

Oprea

et al. 2007

Molecular Cancer Therapeutics

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Aromatase inhibitors (AI) are being evaluated as longterm adjuvant therapies and chemopreventives in breast cancer. However, there are concerns about bone mineral density loss in an estrogen-free environment. Unlike nonsteroidal AIs, the steroidal AI exemestane may exert beneficial effects on bone through its primary metabolite 17-hydroexemestane. We investigated 17-hydroexemestane and observed it bound estrogen receptor A (ERA) very weakly and androgen receptor (AR) strongly. Next, we evaluated 17-hydroexemestane in MCF-7 and T47D breast cancer cells and attributed dependency of its effects on ER or AR using the antiestrogen fulvestrant or the antiandrogen bicalutamide. 17-Hydroexemestane induced proliferation, stimulated cell cycle progression and regulated transcription at high sub-micromolar and micromolar concentrations through ER in both cell lines, but through AR at low nanomolar concentrations selectively in T47D cells. Responses of each cell type to high and low concentrations of the nonaromatizable synthetic androgen R1881 paralleled those of 17-hydroexemestane. 17-Hydroexemestane downregulated ERA protein levels at high concentrations in a cell type -specific manner similarly as 17B-estradiol, and increased AR protein accumulation at low concentrations in both cell types similarly as R1881. Computer docking indicated that the 17B-OH group of 17-hydroexemestane relative to the 17-keto group of exemestane contributed significantly more intermolecular interaction energy toward binding AR than ERA. Molecular modeling also indicated that 17-hydroexemestane interacted with ERA and AR through selective recognition motifs employed by 17B-estradiol and R1881, respectively. We conclude that 17-hydroexemestane exerts biological effects as an androgen. These results may have important implications for long-term maintenance of patients with AIs.

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“…Retrospective clinical studies showed that AR by IHC adds prognostic information beyond the established clinicopathologic parameters in all patient groups and in patients with early-stage ER-positive breast cancer (9,13,14). Tumors coexpressing AR and ER are smaller, have lower Nottingham grade and low proliferative index (14), lymph node involvement is less frequent, and they are more likely to be found in postmenopausal women (4). However, the clinical significance of AR in patients with ER-negative breast cancer is less clear.…”

Section: Introductionmentioning

confidence: 99%

The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data

Božović-Spasojević

Zardavas

Brohée

et al. 2017

Clinical Cancer Research

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Purpose: Androgen receptor (AR) expression has been observed in about 70% of patients with breast cancer, but its prognostic role remains uncertain.Experimental Design: To assess the prognostic role of AR expression in early-stage breast cancer, we performed a metaanalysis of studies that evaluated the impact of AR at the protein and gene expression level on disease-free survival (DFS) and/or overall survival (OS). Eligible studies were identified by systematic review of electronic databases using the MeSH-terms "breast neoplasm" and "androgen receptor" and were selected after a qualitative assessment based on the REMARK criteria. A pooled gene expression analysis of 35 publicly available microarray data sets was also performed from patients with early-stage breast cancer with available gene expression and clinical outcome data.Results: Twenty-two of 33 eligible studies for the clinical meta-analysis, including 10,004 patients, were considered as evaluable for the current study after the qualitative assessment. AR positivity defined by IHC was associated with improved DFS in all patients with breast cancer [multivariate (M) analysis, HR 0.46; 95% confidence interval (CI) 0.37-0.58, P < 0.001] and better OS [M-HR 0.53; 95% CI, 0.38-0.73, P < 0.001]. Thirty-five datasets including 7,220 patients were eligible for the pooled gene expression analysis. High AR mRNA levels were found to confer positive prognosis overall in terms of DFS (HR 0.82; 95% CI 0.72-0.92;P ¼ 0.0007) and OS (HR 0.84; 95% CI, 0.75-0.94; P ¼ 0.02) only in univariate analysis.Conclusions: Our analysis, conducted among more than 17,000 women with early-stage breast cancer included in clinical and gene expression analysis, demonstrates that AR positivity is associated with favorable clinical outcome. Clin Cancer Res; 23(11); 2702-12. Ó2016 AACR.

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The clinical significance of androgen receptors in breast cancer and their relation to histological and cell biological parameters

Cited by 129 publications

References 22 publications

Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer

Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer

Exemestane's 17-hydroxylated metabolite exerts biological effects as an androgen

The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data

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