Conflicting evidence on the frequency of ESR1 amplification in breast cancer
(Impact Factor: 29.35).
08/2008; 40(7):821-2. DOI: 10.1038/ng0708-821
An earlier report of high-frequency ESR1 amplification in breast cancer is now challenged by correspondence from four groups. This discussion of whether or not there is something 'FISHy' about ESR1 amplification highlights the difficulty of validating such observations, leaving the frequency and clinical significance of ESR1 amplification in breast cancer an open question.
Available from: ncbi.nlm.nih.gov
- "Therefore, AR is overexpressed in the majority of breast tumors but its overexpression is not a result of gene amplification as is commonly seen with HER2. Consistent with this finding , recent reports did not find a high rate of ER amplification in breast cancers in contrast to the original report from Holst et al.     . Regardless , the frequency of AR expression in primary breast cancer samples justifies its consideration as a potential therapeutic target. "
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ABSTRACT: Breast cancer occurs at a high frequency in women and, given this fact, a primary focus of breast cancer research has been the study of estrogen receptor α (ER) signaling. However, androgens are known to play a role in normal breast physiology and therefore androgen receptor (AR) signaling is becoming increasingly recognized as an important contributor towards breast carcinogenesis. Moreover, the high frequency of AR expression in breast cancer makes it an attractive therapeutic target, but the ability to exploit AR for therapy has been difficult. Here we review the historical use of androgen/anti-androgen therapies in breast cancer, the challenges of accurately modeling nuclear hormone receptor signaling in vitro, and the presence and prognostic significance of AR in breast cancer.
Available from: Ashani Weeraratna
- "In addition, AR overexpression and AR gene amplification have been reported in prostate cancers . Although ERα gene amplification in breast cancers is controversial , we performed FISH analysis on tissue microarrays (TMAs) with known AR-positive breast cancers using a gene probe for AR and a centromeric chromosome X probe to query for AR gene amplification. There were approximately two copies of AR for every two copies of chromosome X in primary breast cancer samples. "
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ABSTRACT: Although a high frequency of androgen receptor (AR) expression in human breast cancers has been described, exploiting this knowledge for therapy has been challenging. This is in part because androgens can either inhibit or stimulate cell proliferation in pre-clinical models of breast cancer. In addition, many breast cancers co-express other steroid hormone receptors that can affect AR signaling, further obfuscating the effects of androgens on breast cancer cells.
To create better-defined models of AR signaling in human breast epithelial cells, we took estrogen receptor (ER)-α-negative and progesterone receptor (PR)-negative human breast epithelial cell lines, both cancerous and non-cancerous, and engineered them to express AR, thus allowing the unambiguous study of AR signaling. We cloned a full-length cDNA of human AR, and expressed this transgene in MCF-10A non-tumorigenic human breast epithelial cells and MDA-MB-231 human breast-cancer cells. We characterized the responses to AR ligand binding using various assays, and used isogenic MCF-10A p21 knock-out cell lines expressing AR to demonstrate the requirement for p21 in mediating the proliferative responses to AR signaling in human breast epithelial cells.
We found that hyperactivation of the mitogen-activated protein kinase (MAPK) pathway from both AR and epidermal growth factor receptor (EGFR) signaling resulted in a growth-inhibitory response, whereas MAPK signaling from either AR or EGFR activation resulted in cellular proliferation. Additionally, p21 gene knock-out studies confirmed that AR signaling/activation of the MAPK pathway is dependent on p21.
These studies present a new model for the analysis of AR signaling in human breast epithelial cells lacking ERα/PR expression, providing an experimental system without the potential confounding effects of ERα/PR crosstalk. Using this system, we provide a mechanistic explanation for previous observations ascribing a dual role for AR signaling in human breast cancer cells. As previous reports have shown that approximately 40% of breast cancers can lack p21 expression, our data also identify potential new caveats for exploiting AR as a target for breast cancer therapy.
Available from: Roel de Weger
- "FISH seemed to detect more amplifications than MLPA (in this selected group 40% (10/25) plus 12% (3/25) gains). Our percentage of ESR1 amplification by MLPA was much lower than the 20.6% found by Holst et al.  using BAC FISH on tissue microarrays, but was consistent with the lower range (0–10%) of ESR1 amplification reported by other groups using a broad range of techniques such as array comparative genomic hybridization (aCGH), CISH, FISH and qPCR [8–13, 22]. Several reasons have been postulated for the difference in amplification frequencies reported by these techniques including heterogeneity or contamination by normal DNA (aCGH, qPCR, MLPA in this study—although we microdissected the tumor area), the small ESR1 amplicon size (although HER2 also has a small amplicon size: 500–700 kb), low levels of amplification (only 15% of its amplifications were >10 copies, 41% 5–6 copies), large CISH probes (360 kb), and an automated/manual scoring system. "
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ABSTRACT: Expression of estrogen receptor alpha (ERα) is predictive for endocrine therapy response and an important prognostic factor in breast cancer. Overexpression of ERα can be caused by estrogen receptor 1 (ESR1) gene amplification and was originally reported to be a frequent event associated with a significantly longer survival for ER-positive women treated with adjuvant tamoxifen monotherapy, which was however questioned by subsequent studies.
This study aimed to reanalyze the frequency of ESR1 amplification by multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridisation (FISH), and to assess clinicopathologic correlations. MLPA was performed in a group of 135 breast cancer patients, and gains/amplifications were subjected to FISH.
True ESR1 amplification by MLPA was rare (2%) and only 6% more patients showed a modest gain of ESR1. All MLPA-detected ESR1 amplifications and nearly all ESR1 gains were also FISH amplified and gained, but not all FISH amplifications/gains were MLPA amplified/gained, leading to an overall concordance of only 60% between both techniques. All 3 MLPA and FISH ESR1 amplified cases had high ERα expression, but there was no obvious correlation between ESR1 gain and ER status by IHC. ESR1 gains/amplifications were not associated with HER2 gain/amplification, but seemed to be associated with older age. Surprisingly, ESR1 gain/amplification was not associated with low grade as reported previously, but correlated with high grade and high proliferation. Furthermore, ESR1 gain/amplification by MLPA was not associated with nodal status or tumor size (pT status).
ESR1 amplification as detected by MLPA is rare in breast cancer, and seems to be associated with high ERα expression, high age, high grade and high proliferation. This study confirms previous studies that showed differences in the ESR1 amplification frequencies detected by different techniques.
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