Intrinsic breast cancer subtypes defined by estrogen receptor signalling—prognostic relevance of progesterone receptor loss

Braun, Lisa; Mietzsch, F.; Seibold, Petra; Schneeweiß, Andreas; Schirmacher, Peter; Chang‐Claude, Jenny; Sinn, Hans‐Peter; Aulmann, Sebastian

doi:10.1038/modpathol.2013.60

Cited by 49 publications

(42 citation statements)

References 43 publications

(43 reference statements)

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“…23,24 Alternatively, tumors that might be detected as ER negative and/or PR Estrogen receptor-positive/PR-negative tumors are more common in older and postmenopausal women. 7,8,25,26 In this study, ER-positive/PR-negative tumors were most frequent in individuals 60 years or older, whereas ER-negative/PR-positive tumors were most frequent in individuals aged 30 to 49 years. Moreover, we found statistically significant differences in sex and race among the 4 subtypes, a finding that has not been previously reported, to our knowledge.…”

Section: Discussionmentioning

confidence: 51%

Clinicopathological Characteristics and Breast Cancer–Specific Survival of Patients With Single Hormone Receptor–Positive Breast Cancer

Yang

Yin

et al. 2020

JAMA Netw Open

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IMPORTANCE Steroid hormone receptors, including estrogen receptor (ER) and progesterone receptor (PR), are crucial biomarkers in breast cancer (BC). However, limited data are available regarding single hormone receptor-positive (ER-positive/PR-negative and ER-negative/PR-positive) subtypes, rendering treatment decision and survival forecast difficult in patients with these BC subtypes. OBJECTIVE To investigate the clinicopathological characteristics and BC-specific survival (BCSS) of patients with single hormone receptor-positive BC. DESIGN, SETTING, AND PARTICIPANTS In this cohort study, data on patients diagnosed with BC between 1990 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results database (N = 1 158 032). Patients lacking information on ER status, PR status, or BCSS were excluded (n = 334 633). Comparisons were performed between single hormone receptor-positive BC and double hormone receptor-positive/double hormone receptor-negative BC. The dates of analysis were September 1, 2018, to June 31, 2019. MAIN OUTCOMES AND MEASURES The BCSS of patients with single hormone receptor-positive BC. RESULTS This cohort study included 823 399 patients with BC (818 002 women and 5397 men). The median (range) age at diagnosis was 60 (8-108) years, and the median (range) follow-up duration was 71 (0-311) months. The percentages of ER-positive/PR-positive, ER-positive/PRnegative, ER-negative/PR-positive, and ER-negative/PR-negative cases were 67.2%, 12.2%, 1.6%, and 19.0%, respectively. Single hormone receptor-positive subtypes showed distinct clinical characteristics compared with double hormone receptor-positive/double hormone receptornegative subtypes. Multivariable Cox proportional hazards regression analysis showed that patients with ER-positive/PR-negative (hazard ratio [HR], 1.36; 95% CI, 1.34-1.38) and ER-negative/PRpositive (HR, 1.61; 95% CI, 1.55-1.67) tumors had worse BCSS than patients with the ER-positive/PRpositive subtype. In contrast, patients with ER-positive/PR-negative (HR, 1.27; 95% CI, 1.24-1.29) and ER-negative/PR-positive (HR, 1.07; 95% CI, 1.03-1.11) tumors had better BCSS than patients with the ER-negative/PR-negative subtype. The BCSS was statistically significantly worse in patients with ER-negative/PR-positive tumors than in patients with ER-positive/PR-negative tumors (HR, 1.18; 95% CI, 1.14-1.23). CONCLUSIONS AND RELEVANCE In this cohort study, statistically significant distinctions between survival rates of patients with single hormone receptor-positive BC vs double hormone receptorpositive/double hormone receptor-negative BC were observed. Different strategies may be required (continued)

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Section: Discussionmentioning

confidence: 51%

Clinicopathological Characteristics and Breast Cancer–Specific Survival of Patients With Single Hormone Receptor–Positive Breast Cancer

Yang

Yin

et al. 2020

JAMA Netw Open

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“…The overexpression of 67 of them was associated with poor metastatic-free survival (MFS) in luminal tumors (p<0.05; FDR<0.25). While several data show that loss of PR expression is an important predictor of poor patient outcome in ER+ BCs [48], [49], 94% (61/67) of our luminal B candidates were pertinent predictor independently of the PR status ( Table S3M ).…”

Section: Resultsmentioning

confidence: 83%

“…M : The overexpression of 67 “luminal B core” candidate oncogenes is associated with poor MFS. A data comparison was done with those obtained for tumors classified with PAM50 SSP [48]. N : Mutually exclusive and co-occurring luminal B CNAs.…”

Section: Supporting Informationmentioning

confidence: 99%

Candidate Luminal B Breast Cancer Genes Identified by Genome, Gene Expression and DNA Methylation Profiling

et al. 2014

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Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15) and UTRN (6q24), were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype.

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“…A second estrogen receptor, ERβ ( ESR2 ), was discovered in 1996 (Kuiper, et al 1996; Mosselman, et al 1996) and is the predominant ER in normal breast (Kuiper et al 1996). Clinical studies show that whereas ERβ expression decrease during tumor progression (Koehler, et al 2005; Palmieri, et al 2002; Roger, et al 2001; Speirs, et al 2002; Zhao, et al 2008), a large proportion, between 39% and 77%, of all breast cancer tumors co-express both ERs (Braun, et al 2013; Fuqua, et al 2003; Honma, et al 2008; Li, et al 2010a; Marotti, et al 2010; Murphy and Leygue 2012; Novelli, et al 2008; O'Neill, et al 2004; Powell, et al 2012; Saunders 2006; Shaaban, et al 2008; Shaaban, et al 2003; Speirs, et al 2004). ERβ is therefore a potential marker and target, in these tumors, that could enhance the use of endocrine therapy.…”

Section: Introductionmentioning

confidence: 99%

Support of a bi-faceted role of estrogen receptor β (ERβ) in ERα-positive breast cancer cells

Jonsson¹,

Katchy²,

Williams³

2013

Endocrine-Related Cancer

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Expression of estrogen receptor alpha (ERα) in breast cancer identifies patients most likely to respond to endocrine treatment. The second estrogen receptor, ERβ, is also expressed in breast tumors, but its function and therapeutic potential needs further study. Whereas in vitro studies have established that ERβ opposes transcriptional and proliferative functions of ERα, several clinical studies report its correlation to proliferative markers and poorer prognosis. The data demonstrating that ERβ opposes ERα are primarily based on transient expression of ERβ. Here, we explored the functions of constitutively expressed ERβ in ERα-positive breast cancer lines MCF7 and T47D. We found that ERβ, under these conditions heterodimerized with ERα in presence and absence of 17β-estradiol, and induced genome-wide transcriptional changes. Widespread anti-ERα signaling was, however, not observed and ERβ was not anti-proliferative. Tamoxifen antagonized proliferation and ER-mediated gene regulation both in the presence and absence of ERβ. In conclusion, ERβ’s role in cells adapted to its expression appears to differ from its role in cells with transient expression. Our study is important because it provides a deeper understanding of ERβ’s role in breast tumors that co-express both receptors and supports an emerging bi-faceted role of ERβ.

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Intrinsic breast cancer subtypes defined by estrogen receptor signalling—prognostic relevance of progesterone receptor loss

Cited by 49 publications

References 43 publications

Clinicopathological Characteristics and Breast Cancer–Specific Survival of Patients With Single Hormone Receptor–Positive Breast Cancer

Clinicopathological Characteristics and Breast Cancer–Specific Survival of Patients With Single Hormone Receptor–Positive Breast Cancer

Candidate Luminal B Breast Cancer Genes Identified by Genome, Gene Expression and DNA Methylation Profiling

Support of a bi-faceted role of estrogen receptor β (ERβ) in ERα-positive breast cancer cells

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