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      L1CAM is expressed in triple-negative breast cancers and is inversely correlated with Androgen receptor

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          Abstract

          Background

          Breast cancer is a heterogeneous disease displaying distinct molecular features and clinical outcome. The molecular profile of triple-negative breast cancers (TNBCs) overlaps with that of basal-like breast cancers that in turn show similarities with high-grade serous ovarian and endometrial carcinoma. L1CAM is an established biomarker for the latter cancers and we showed before that approximately 18% of primary breast cancers are positive for L1CAM and have a bad prognosis. Here we analysed the expression of L1CAM breast cancer subtypes.

          Methods

          We analyzed mRNA and protein expression data from different breast cancer cohorts for L1CAM, estrogen receptor, progesterone receptor, Her-2 and Androgen receptor (AR) and correlated the data. We performed Western blot analysis on tumor cell lysates and carried out chromatin-immuno-precipitation (CHIP) after AR overexpression.

          Results

          We find that L1CAM is expressed preferentially though not exclusively in TNBCs. Using the human cancer genome atlas database and two independent breast cancer cohorts we find that L1CAM is inversely correlated with androgen receptor (AR) expression. We found that L1CAM highAR low primary breast tumors have the worst clinical outcome. Overexpression of AR in MDA-MB436 breast cancer cells decreased L1CAM expression at the protein and mRNA level and CHIP-analysis revealed binding of AR to the L1CAM promoter region.

          Conclusions

          These results suggest that L1CAM in breast cancer is under AR control. The data also strongly advocate the use of L1CAM assessment in breast cancer diagnosis. We suggest that L1CAM expression could be causally related to the bad prognosis of TNBCs.

          Electronic supplementary material

          The online version of this article (doi:10.1186/1471-2407-14-958) contains supplementary material, which is available to authorized users.

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          Most cited references23

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          Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype.

          Basal-like breast cancer is associated with high grade, poor prognosis, and younger patient age. Clinically, a triple-negative phenotype definition [estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (HER)-2, all negative] is commonly used to identify such cases. EGFR and cytokeratin 5/6 are readily available positive markers of basal-like breast cancer applicable to standard pathology specimens. This study directly compares the prognostic significance between three- and five-biomarker surrogate panels to define intrinsic breast cancer subtypes, using a large clinically annotated series of breast tumors. Four thousand forty-six invasive breast cancers were assembled into tissue microarrays. All had staging, pathology, treatment, and outcome information; median follow-up was 12.5 years. Cox regression analyses and likelihood ratio tests compared the prognostic significance for breast cancer death-specific survival (BCSS) of the two immunohistochemical panels. Among 3,744 interpretable cases, 17% were basal using the triple-negative definition (10-year BCSS, 6 7%) and 9% were basal using the five-marker method (10-year BCSS, 62%). Likelihood ratio tests of multivariable Cox models including standard clinical variables show that the five-marker panel is significantly more prognostic than the three-marker panel. The poor prognosis of triple-negative phenotype is conferred almost entirely by those tumors positive for basal markers. Among triple-negative patients treated with adjuvant anthracycline-based chemotherapy, the additional positive basal markers identified a cohort of patients with significantly worse outcome. The expanded surrogate immunopanel of estrogen receptor, progesterone receptor, human HER-2, EGFR, and cytokeratin 5/6 provides a more specific definition of basal-like breast cancer that better predicts breast cancer survival.
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            The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis.

            The androgen receptor (AR) is a key regulator of prostate growth and the principal drug target for the treatment of prostate cancer. Previous studies have mapped AR targets and identified some candidates which may contribute to cancer progression, but did not characterize AR biology in an integrated manner. In this study, we took an interdisciplinary approach, integrating detailed genomic studies with metabolomic profiling and identify an anabolic transcriptional network involving AR as the core regulator. Restricting flux through anabolic pathways is an attractive approach to deprive tumours of the building blocks needed to sustain tumour growth. Therefore, we searched for targets of the AR that may contribute to these anabolic processes and could be amenable to therapeutic intervention by virtue of differential expression in prostate tumours. This highlighted calcium/calmodulin-dependent protein kinase kinase 2, which we show is overexpressed in prostate cancer and regulates cancer cell growth via its unexpected role as a hormone-dependent modulator of anabolic metabolism. In conclusion, it is possible to progress from transcriptional studies to a promising therapeutic target by taking an unbiased interdisciplinary approach.
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              Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists.

              Breast cancer is a heterogeneous disease encompassing a variety of entities with distinct morphological features and clinical behaviors. Although morphology is often associated with the pattern of molecular aberrations in breast cancers, it is also clear that tumors of the same histological type show remarkably different clinical behavior. This is particularly true for 'basal-like cancer', which is an entity defined using gene expression analysis. The purpose of this article was to review the current state of knowledge of basal-like breast cancers, to discuss the relationship between basal-like and triple-negative breast cancers, and to clarify practical implications of these diagnoses for pathologists and oncologists.
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                Author and article information

                Contributors
                k.doberstein@dkfz.de
                milde@uke.de
                NBRETZ@partners.org
                u.schirmer@dkfz.de
                Ayelethar@clalit.org.il
                iwitzel@uke.de
                abenarie@hotmail.com
                Michael.hubalek@i-med.ac.at
                Elisabeth.mueller@i-med.ac.at
                Susanne.Reinold@i-med.ac.at
                Alain.zeimet@i-med.ac.at
                p.altevogt@dkfz.de
                Mina_F@clalit.org.il
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                15 December 2014
                2014
                : 14
                : 1
                : 958
                Affiliations
                [ ]Tumor Immunology Programme, D015, German Cancer Research Center, Heidelberg, Germany
                [ ]Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
                [ ]Chemical Laboratories, Kaplan Medical Center, Rehovot, Israel
                [ ]Department of Gynecology, Kaplan Medical Center, Rehovot, Israel
                [ ]Department of Gynecology and Obstetrics, Medical University of Innsbruck, 6020 Innsbruck, Austria
                [ ]Institute of Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
                Article
                5172
                10.1186/1471-2407-14-958
                4301892
                25510351
                76646eb6-5949-403e-ae5c-83cdb151b9d0
                © Doberstein et al.; licensee BioMed Central. 2014

                This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 8 September 2014
                : 11 December 2014
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2014

                Oncology & Radiotherapy
                triple-negative,basal-like,er/pr,emt,ar
                Oncology & Radiotherapy
                triple-negative, basal-like, er/pr, emt, ar

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