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      Vitamin D receptor, Retinoid X receptor and peroxisome proliferator-activated receptor γ are overexpressed in BRCA1 mutated breast cancer and predict prognosis

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          Abstract

          Background

          BRCA1 mutated breast cancers are commonly diagnosed as negative for classical hormone receptors i.e. estrogen receptor, progesterone receptor and/or Her2. Due to these common targets being absent the application of anti-endocrine therapies is rather limited and a certain focus has been set on discovering alternative target molecules. We recently highlighted thyroid hormone receptors (TRs) to predict prognosis in breast cancer patients that had been diagnosed a BRCA1 germline mutation. Vitamin D Receptor (VDR), Retinoid X Receptor (RXR) and Peroxisome Proliferator-activated Receptor γ (PPARγ) are known to interact with TRs by forming functional heterodimers. Whether VDR, RXR or PPARγ are expressed in BRCA1 mutated breast cancer or may even be present in case of triple negativity is not known. Hence the current study aimed to investigate VDR, RXR and PPARγ in BRCA1 mut breast cancer and to test whether any of the three may be associated with clinico-pathological criteria including overall survival.

          Methods

          This study analyzed VDR, RXR and PPARγ by immunohistochemistry in BRCA1 associated ( n = 38) and sporadic breast cancer ( n = 79). Receptors were quantified by applying an established scoring system (IR-score) and were tested for association with clinico-pathological variables.

          Results

          VDR, RXR and PPARγ were detected in over 90% of triple negative BRCA1 mut breast cancer and were significantly (VDR: p < 0.001, RXR: p = 0.010, PPARγ: p < 0.001) overexpressed in BRCA1 mutated as compared to sporadic cancer cases. VDR and RXR positivity predicted prolonged overall survival only in BRCA1 mutated cases while such association was not observed in sporadic breast cancer.

          Conclusions

          In conclusion, this is the first study to describe VDR, RXR and PPARγ in BRCA1 mutated breast cancer. Based on the data presented here these receptors may be hypothesized to potentially evolve as interesting markers or even targets in hereditary breast cancer. However, independent studies are indispensable thus to confirm this hypothesis.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13046-017-0517-1) contains supplementary material, which is available to authorized users.

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          Most cited references31

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          Reporting recommendations for tumor marker prognostic studies.

          Lisa McShane, Douglas G. Altman, Willi Sauerbrei … (2005)
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            Genetic susceptibility to triple-negative breast cancer.

            Celine M Vachon, Claire N. Stevens, Fergus Couch (2013)
            Triple-negative breast cancers (TNBC), defined by the absence of estrogen receptor, progesterone receptor, and HER-2 expression, account for 12% to 24% of all breast cancers. TNBC is associated with early recurrence of disease and poor outcome. Germline mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes have been associated with up to 15% of TNBC, and TNBC accounts for 70% of breast tumors arising in BRCA1 mutation carriers and 16% to 23% of breast tumors in BRCA2 carriers. Whether germline mutations in other breast cancer susceptibility genes also predispose to TNBC remains to be determined. Common variation in a subset of the 72 known breast cancer susceptibility loci identified through genome-wide association studies and other large-scale genotyping efforts have also been associated with risk of TNBC (TOX3, ESR1, RAD51L1, TERT, 19p13.1, 20q11, MDM4, 2p24.1, and FTO). Furthermore, variation in the 19p13.1 locus and the MDM4 locus has been associated with TNBC, but not other forms of breast cancer, suggesting that these are TNBC-specific loci. Thus, TNBC can be distinguished from other breast cancer subtypes by a unique pattern of common and rare germline predisposition alleles. Additional efforts to combine genetic and epidemiologic data are needed to better understand the etiology of this aggressive form of breast cancer, to identify prevention and therapeutic targets, and to impact clinical practice through the development of risk prediction models. ©2012 AACR.
            Article 0 comments Cited 94 times – based on 0 reviews     Review now
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              Immunohistochemistry of estrogen and progesterone receptors reconsidered: experience with 5,993 breast cancers.

              Mehrdad Nadji, Carmen R. Gomez-Fernandez, Parvin Ganjei-Azar … (2005)
              Paraffin sections or fine-needle aspiration smears from 5,993 cases of invasive mammary carcinomas were assessed immunohistochemically for estrogen receptor (ER; 1D5) and progesterone receptor (PR; 636) expression. Staining pattern and intensity were correlated with histologic subtypes and nuclear grades of tumors. Positive nuclear staining for ER and PR was observed in 75% and 55% of invasive carcinomas, respectively. In 92% of ER+ cases, diffuse and uniform staining of most tumor cells was observed. In the remaining 8%, a focal ER reaction was seen, usually because of inadequate fixation. In 21% of PR+ tumors, the reaction was heterogeneous or focal but unrelated to fixation. There were no ER-, PR+ tumors. All pure tubular, colloid, and infiltrating lobular carcinomas were ER+. All medullary, apocrine, and metaplastic and most high-nuclear-grade carcinomas were ER-. With monoclonal antibody 1D5 and antigen retrieval, immunohistochemical reaction for ER in breast cancer usually is an all-or-none phenomenon; therefore, quantitation of results is unnecessary. Despite antigen retrieval, inadequate fixation can cause false-negative results; evaluation of internal positive control samples is imperative. ER positivity and negativity are predictable in certain histologic types and nuclear grades of breast cancer. The reaction for PR can be heterogeneous or focal.
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                Author and article information

                Contributors
                Sabine Heublein: sabine.heublein@med.uni-heidelberg.de
                Doris Mayr: doris.mayr@med.uni-muenchen.de
                Alfons Meindl: alfons.meindl@lrz.tu-muenchen.de
                Alexandra Kircher: alexandra.kircher@slk.kliniken.de
                Udo Jeschke: udo.jeschke@med.uni-muenchen.de
                Nina Ditsch: nina.ditsch@med.uni-muenchen.de
                Journal
                Journal ID (nlm-ta): J Exp Clin Cancer Res
                Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res
                Title: Journal of Experimental & Clinical Cancer Research : CR
                Publisher: BioMed Central (London )
                ISSN (Print): 0392-9078
                ISSN (Electronic): 1756-9966
                Publication date (Electronic): 20 April 2017
                Publication date PMC-release: 20 April 2017
                Publication date Collection: 2017
                Volume: 36
                Electronic Location Identifier: 57
                Affiliations
                [1 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Department of Obstetrics and Gynaecology - National Center for Tumor Diseases (NCT), , Heidelberg University Hospital, ; Heidelberg, Germany
                [2 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Department of Obstetrics and Gynecology, , Ludwig-Maximilians-University of Munich, ; Munich, Germany
                [3 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Department of Pathology, , Ludwig-Maximilians-University of Munich, ; Munich, Germany
                [4 ]ISNI 0000000123222966, GRID grid.6936.a, Department of Obstetrics and Gynecology, , Technical University of Munich, ; Munich, Germany
                [5 ]Department of Internal Medicine, SLK-Kliniken Heilbronn GmbH, Heilbronn, Germany
                Article
                Publisher ID: 517
                DOI: 10.1186/s13046-017-0517-1
                PMC ID: 5399435
                PubMed ID: 28427429
                SO-VID: 357f0046-9ab2-4c9b-a8d2-e7ee7a4e0e16
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis 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. 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
                Date received : 3 November 2016
                Date accepted : 17 March 2017
                Funding
                Funded by: Deutschlandstipendium
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: vitamin d receptor (vdr),retinoid x receptor (rxr),peroxisome-proliferator activated receptor γ (pparγ),hereditary breast cancer,survival,brca1
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: vitamin d receptor (vdr), retinoid x receptor (rxr), peroxisome-proliferator activated receptor γ (pparγ), hereditary breast cancer, survival, brca1

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