Androgen Receptor Expression and Breast Cancer Survival in Postmenopausal Women

Hu, Rong; Dawood, Shaheenah; Holmes, Michelle D.; Collins, Laura C.; Schnitt, Stuart J.; Cole, Kimberley; Marotti, Jonathan D.; Hankinson, Susan E.; Colditz, Graham A.; Tamimi, Rulla M.

doi:10.1158/1078-0432.ccr-10-2021

Cited by 336 publications

(355 citation statements)

References 30 publications

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“…In the former, a strong better prognostication was conferred by AR positivity among patients with ER þ breast cancer both in univariate and multivariate analysis, which is in line with previously published studies (8,9,11,41,42,53). Preclinical evidence suggesting an AR-ER cross-talk also support these findings, indicating that AR can antagonize ER signaling depending on the relative levels of these two steroid receptors (2).…”

Section: Discussionsupporting

confidence: 87%

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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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Section: Discussionsupporting

confidence: 87%

“…Twenty studies (6-9, 11, 39-52) were evaluable for the DFS and sixteen (7-9, 11, 39-42, 44-49, 53, 54) for the OS (Supplementary Tables S2A and S2B); among studies only two (44,53) were prospective, the rest was retrospective.…”

Section: Clinical Meta-analysismentioning

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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“…The NHS is a prospective cohort study initiated in 1976: 121,700 female US-registered nurses between the ages of 30 and 55 y completed a questionnaire on factors relevant to women's health with follow-up biennial questionnaires used to update exposure information and ascertain nonfatal incident diseases (41). See SI Materials and Methods for additional information about the cohort, selection criteria for outcome analysis, the covariates evaluated, and the statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

“…The NHS breast cancer tissue-block collection and TMA assembly have been described previously (41,42). Paraffin blocks were also obtained from the archives of Brigham and Women's Hospital to generate a TMA of normal breast epithelial lobules.…”

Section: Methodsmentioning

confidence: 99%

High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer

Santagata

Lin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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279

273

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Heat-shock factor 1 (HSF1) is the master transcriptional regulator of the cellular response to heat and a wide variety of other stressors. We previously reported that HSF1 promotes the survival and proliferation of malignant cells. At this time, however, the clinical and prognostic significance of HSF1 in cancer is unknown. To address this issue breast cancer samples from 1,841 participants in the Nurses' Health Study were scored for levels of nuclear HSF1. Associations of HSF1 status with clinical parameters and survival outcomes were investigated by Kaplan-Meier analysis and Cox proportional hazard models. The associations were further delineated by Kaplan-Meier analysis using publicly available mRNA expression data. Our results show that nuclear HSF1 levels were elevated in ∼80% of in situ and invasive breast carcinomas. In invasive carcinomas, HSF1 expression was associated with high histologic grade, larger tumor size, and nodal involvement at diagnosis (P < 0.0001). By using multivariate analysis to account for the effects of covariates, high HSF1 levels were found to be independently associated with increased mortality (hazards ratio: 1.62; 95% confidence interval: 1.21-2.17; P < 0.0013). This association was seen in the estrogen receptor (ER)-positive population (hazards ratio: 2.10; 95% confidence interval: 1.45-3.03; P < 0.0001). In public expression profiling data, high HSF1 mRNA levels were also associated with an increase in ER-positive breast cancerspecific mortality. We conclude that increased HSF1 is associated with reduced breast cancer survival. The findings indicate that HSF1 should be evaluated prospectively as an independent prognostic indicator in ER-positive breast cancer. HSF1 may ultimately be a useful therapeutic target in cancer.heat-shock protein 90 | signature | pathology | heat-shock response | immunohistochemistry H eat-shock factor 1 (HSF1) is a multifaceted transcription factor that governs the cellular response to disruptions in protein homeostasis. To protect the proteome under various physiologic stresses, HSF1 drives the production of classic heatshock proteins (HSPs), such as HSP27, HSP70, and HSP90, that act as protein chaperones. This heat-shock response is an ancient adaptive mechanism that is present in eukaryotes from yeast to humans (1-3). The functions of HSF1 are not limited to increasing the expression of chaperones, however. HSF1 also modulates the expression of hundreds of genes other than chaperones that are critical for survival under an array of potentially lethal stressors (4, 5). As a result, HSF1 influences fundamental cellular processes such as cell-cycle control, protein translation, and glucose metabolism (5, 6).We have demonstrated that the multifaceted ability of HSF1 to promote survival in the face of lethal stressors is co-opted by cancer cells (6). In the malignant state, a litany of stressful conditions arises from the tumor microenvironment and from drastic internal changes in core cellular physiology that are hallmarks of cancer (7,8). HSF1 permit...

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“…However, the role of androgen signaling in ER+ breast cancer is less clear. Expression of AR is associated with good prognosis in ER+ breast cancer (Hu et al 2011, Hilborn et al 2016, with anti-estrogenic and anti-proliferative effects in ER+ breast cancer being reported (Peters et al 2009. The anti-proliferative effect of AR is partly attributed to its inhibitory effect on ESR1 signaling in ER+ breast cancer cells (Peters et al 2009, Fioretti et al 2014.…”

Section: Nr Expression In Breast Cancer Subtypesmentioning

confidence: 99%

Emerging functional roles of nuclear receptors in breast cancer

Doan

Graham

2017

Journal of Molecular Endocrinology

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Nuclear receptors (NRs) have been targets of intensive drug development for decades due to their roles as key regulators of multiple developmental, physiological and disease processes. In breast cancer, expression of the estrogen and progesterone receptor remains clinically important in predicting prognosis and determining therapeutic strategies. More recently, there is growing evidence supporting the involvement of multiple nuclear receptors other than the estrogen and progesterone receptors, in the regulation of various processes important to the initiation and progression of breast cancer. We review new insights into the mechanisms of action of NRs made possible by recent advances in genomic technologies and focus on the emerging functional roles of NRs in breast cancer biology, including their involvement in circadian regulation, metabolic reprogramming and breast cancer migration and metastasis.

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Androgen Receptor Expression and Breast Cancer Survival in Postmenopausal Women

Cited by 336 publications

References 30 publications

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

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

High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer

Emerging functional roles of nuclear receptors in breast cancer

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