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      Elevated Aromatase ( CYP19A1) Expression Is Associated with a Poor Survival of Patients with Estrogen Receptor Positive Breast Cancer

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          Abstract

          Genetic variants in CYP19A1, the gene encoding aromatase, have been reported to be associated with circulating estrogen concentrations, a key risk factor for breast cancer. The mechanism underlying this association is still unclear; it has been suggested that some of these variants may alter the expression and/or activity of aromatase. Here we analyzed the expression of intra-tumoral CYP19A1 messenger RNA (mRNA) and the genotypes of rs10046, a well-characterized single nucleotide polymorphism in CYP19A1, in 138 breast cancer patients and 15 breast cancer cell lines. The genotype TT was detected in 36 patients and six cell lines, genotype CT in 55 patients and five cell lines, and genotype CC in 28 patients and four cell lines. We found no evidence for a significant association of CYP19A1 levels with rs10046 genotypes, although expression tended to be higher in tumors and cell lines with the homozygous risk genotype TT. We also found no evidence for a significant association of rs10046 genotypes with breast cancer prognosis. In contrast, high CYP19A1 expression was highly significantly associated with a poor overall, disease-free, and metastasis-free survival in estrogen receptor-positive but not negative breast cancer patients. Moreover, CYP19A1 mRNA was significantly elevated in postmenopausal patients and in patients older than 50 years, and a trend towards a positive correlation with ER status and ESR1 mRNA expression was observed. These findings highlight the key role of aromatase in estrogen receptor-positive breast cancer biology.

          Electronic supplementary material

          The online version of this article (10.1007/s12672-017-0317-2) contains supplementary material, which is available to authorized users.

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          Most cited references 60

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          A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes.

          Recent studies suggest that thousands of genes may contribute to breast cancer pathophysiologies when deregulated by genomic or epigenomic events. Here, we describe a model "system" to appraise the functional contributions of these genes to breast cancer subsets. In general, the recurrent genomic and transcriptional characteristics of 51 breast cancer cell lines mirror those of 145 primary breast tumors, although some significant differences are documented. The cell lines that comprise the system also exhibit the substantial genomic, transcriptional, and biological heterogeneity found in primary tumors. We show, using Trastuzumab (Herceptin) monotherapy as an example, that the system can be used to identify molecular features that predict or indicate response to targeted therapies or other physiological perturbations.
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            Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies.

             P Appleby,  Karen Barnes,   (2002)
            Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk. We reanalyzed the worldwide data from prospective studies to examine the relationship between the levels of endogenous sex hormones and breast cancer risk in postmenopausal women. We analyzed the individual data from nine prospective studies on 663 women who developed breast cancer and 1765 women who did not. None of the women was taking exogenous sex hormones when their blood was collected to determine hormone levels. The relative risks (RRs) for breast cancer associated with increasing hormone concentrations were estimated by conditional logistic regression on case-control sets matched within each study. Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate. The risk for breast cancer increased statistically significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non-sex hormone-binding globulin (SHBG)-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. The RRs for women with increasing quintiles of estradiol concentrations, relative to the lowest quintile, were 1.42 (95% confidence interval [CI] = 1.04 to 1.95), 1.21 (95% CI = 0.89 to 1.66), 1.80 (95% CI = 1.33 to 2.43), and 2.00 (95% CI = 1.47 to 2.71; P(trend)<.001); the RRs for women with increasing quintiles of free estradiol were 1.38 (95% CI = 0.94 to 2.03), 1.84 (95% CI = 1.24 to 2.74), 2.24 (95% CI = 1.53 to 3.27), and 2.58 (95% CI = 1.76 to 3.78; P(trend)<.001). The magnitudes of risk associated with the other estrogens and with the androgens were similar. SHBG was associated with a decrease in breast cancer risk (P(trend) =.041). The increases in risk associated with increased levels of all sex hormones remained after subjects who were diagnosed with breast cancer within 2 years of blood collection were excluded from the analysis. Levels of endogenous sex hormones are strongly associated with breast cancer risk in postmenopausal women.
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              Breast cancer

              Breast cancer is one of the three most common cancers worldwide. Early breast cancer is considered potentially curable. Therapy has progressed substantially over the past years with a reduction in therapy intensity, both for locoregional and systemic therapy; avoiding overtreatment but also undertreatment has become a major focus. Therapy concepts follow a curative intent and need to be decided in a multidisciplinary setting, taking molecular subtype and locoregional tumour load into account. Primary conventional surgery is not the optimal choice for all patients any more. In triple-negative and HER2-positive early breast cancer, neoadjuvant therapy has become a commonly used option. Depending on clinical tumour subtype, therapeutic backbones include endocrine therapy, anti-HER2 targeting, and chemotherapy. In metastatic breast cancer, therapy goals are prolongation of survival and maintaining quality of life. Advances in endocrine therapies and combinations, as well as targeting of HER2, and the promise of newer targeted therapies make the prospect of long-term disease control in metastatic breast cancer an increasing reality.
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                Author and article information

                Contributors
                +43-1-40400-27380 , martin.schreiber@muv.ac.at
                Journal
                Horm Cancer
                Horm Cancer
                Hormones & Cancer
                Springer US (New York )
                1868-8497
                1868-8500
                23 January 2018
                23 January 2018
                2018
                : 9
                : 2
                : 128-138
                Affiliations
                [1 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Obstetrics & Gynecology, , Medical University of Vienna, ; Waehringer Guertel 18-20/5Q, 1090 Vienna, Austria
                [2 ]University of Applied Sciences, 1030 Vienna, Austria
                [3 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Comprehensive Cancer Center, , Medical University of Vienna, ; 1090 Vienna, Austria
                Article
                317
                10.1007/s12672-017-0317-2
                5862917
                29363090
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funding
                Funded by: Austrian Ministry of Science, Research and Economy (Austrian Genome Research Program GEN-AU)
                Funded by: Anniversary Fund of the “Oesterreichische Nationalbank”
                Award ID: 12994
                Award Recipient :
                Categories
                Original Paper
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2018

                Oncology & Radiotherapy

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