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      Trop-2 Is a Determinant of Breast Cancer Survival

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          Abstract

          Trop-2 is a calcium signal transducer that drives tumor growth. Anti-Trop-2 antibodies with selective reactivity versus Trop-2 maturation stages allowed to identify two different pools of Trop-2, one localized in the cell membrane and one in the cytoplasm. Of note, membrane-localized/functional Trop-2 was found to be differentially associated with determinants of tumor aggressiveness and distinct breast cancer subgroups. These findings candidated Trop-2 states to having an impact on cancer progression. We tested this model in breast cancer. A large, consecutive human breast cancer case series (702 cases; 8 years median follow-up) was analyzed by immunohistochemistry with anti-Trop-2 antibodies with selective reactivity for cytoplasmic-retained versus functional, membrane-associated Trop-2. We show that membrane localization of Trop-2 is an unfavorable prognostic factor for overall survival (1+ versus 0 for all deaths: hazard ratio, 1.63; P = 0.04), whereas intracellular Trop-2 has a favorable impact on prognosis, with an adjusted hazard ratio for all deaths of 0.48 (high versus low; P = 0.003). A corresponding impact of intracellular Trop-2 was found on disease relapse (high versus low: hazard ratio, 0.51; P = 0.004). Altogether, we demonstrate that the Trop-2 activation states are critical determinants of tumor progression and are powerful indicators of breast cancer patients survival.

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          Most cited references 27

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          Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases.

          To determine whether progesterone receptor (PgR) status provides additional value to estrogen receptor (ER) status and improves prediction of benefit from endocrine treatment among patients with primary breast cancer. Clinical outcomes of patients in two large databases were analyzed as a function of steroid receptor status. The first database (PP), contained 3,739 patients who did not receive any systemic adjuvant therapy and 1,688 patients who received adjuvant endocrine therapy but no chemotherapy. The second database (SPORE), contained 10,444 patients who received adjuvant endocrine therapy but no chemotherapy. Biochemical ER and PgR assays were identically performed in two different central laboratories. In univariate and multivariate analyses, the prognostic significance of PgR status among systemically untreated patients is modest. Among endocrine-treated patients, however, multivariate analyses, including lymph-node involvement, tumor size, and age, demonstrate that PgR status is independently associated with disease-free and overall survival. For recurrence, the reduction in relative risk (RR) was 25% for ER-positive/PgR-negative patients and 53% for ER-positive/PgR-positive patients, compared with ER-negative/PgR-negative patients (P <.0001, PP patients). Patients with ER-positive/PgR-negative tumors have a reduction in RR of death of 30% (SPORE patients) and 38% (PP patients), compared with patients with ER-negative/PgR-negative tumors (P <.0001). For ER-positive/PgR-positive tumors, the reduction of the risk of death was greater than 46% in SPORE patients and 58% in PP patients, indicating that ER-positive/PgR-positive patients derive more benefit from endocrine therapy (P <.0001). When accurately measured, PgR status is an independent predictive factor for benefit from adjuvant endocrine therapy. Therefore, PgR status should be taken into account when discussing RR reductions expected from endocrine treatment with individual patients.
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            Human Trop-2 is a tumor-associated calcium signal transducer.

            Trop-2/EGP-1/GA733-1 is a recently identified cell surface glycoprotein highly expressed by human carcinomas. The cytoplasmic tail of Trop-2 possesses potential serine and tyrosine phosphorylation sites and a phosphatidyl-inositol binding consensus sequence. Thus, we investigated whether Trop-2 might be a functional signaling molecule. Using the fluorescent probe Fura-2, we assayed the cytoplasmic calcium levels in human cancer cells stimulated with anti-Trop-2 or control antibodies. Three anti-Trop-2 MAbs, Rs7-7G11, MOv16 and 162-46.2 specifically induced a transient intracellular calcium level increment in up to 40% of the experiments performed. Polyclonal antisera recognizing recombinant Trop-2 molecules possessed a much lower stimulation efficiency. The average latency of antibody-induced Ca2+ rise for OvCa-432 cells was 64+/-26 sec. Internal Ca2+ concentrations reached peaks of 190+/-24 nM vs. basal levels of 61+/-4 nM and returned to baseline within 193+/-37 sec. Similar values were obtained in MCF-7 cells. For comparison, stimulation of P2-purinergic receptors on MCF-7 and OvCa-432 cells induced a Ca2+ rise in most cases, leading to average internal Ca2+ concentrations of 297+/-41 and 391+/-39 nM, respectively. Our findings show that Trop-2 transduces an intracellular calcium signal, are consistent with the hypothesis that it acts as a cell surface receptor and support a search for a physiological ligand.
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              Human trophoblast cell-surface antigens defined by monoclonal antibodies.

              A series of monoclonal antibodies has been raised against the human choriocarcinoma cell-line, BeWo. Four antigens, Trop-1, -2, -3, and -4, are defined on normal and malignant trophoblast cells. Trop-1 and Trop-2 appear to be specifically expressed on syncytio- and cytotrophoblasts, whereas Trop-3 and Trop-4 are also detected on various tumor cell lines, normal lymphocytes, and monocytes. Anti-Trop-1 and anti-Trop-2 antibodies might prove useful for detection and isolation of fetal trophoblast cells circulating in pregnant women's blood and for diagnosis and therapy in patients having choriocarcinomas and other germ-cell neoplasms.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                13 May 2014
                : 9
                : 5
                Affiliations
                [1 ]Unit of Medical Statistics, Biometry and Bioinformatics “Giulio A. Maccacaro”, Department of Clinical Sciences and Community Health, University of Milan, Milano, Italy
                [2 ]Unit of Cancer Pathology, Department of Biomedical Sciences and CeSI, Fondazione ‘G. D'Annunzio’, University of Chieti, Chieti, Italy
                [3 ]MediaPharma s.r.l., CeSI, University ‘G. D'Annunzio’, Chieti, Italy
                [4 ]Section of Surgical Pathology, Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy
                [5 ]Fondazione IRCCS, Istituto Nazionale Tumori, Milano, Italy
                [6 ]Department of Neurosciences, Imaging and Clinical Sciences – Physiology and Physiopathology, University of Chieti, Chieti, Italy
                [7 ]Oncoxx Biotech s.r.l., Chieti, Italy
                University of Dundee, United Kingdom
                Author notes

                Competing Interests: This study was partly funded by Oncoxx Biotech, and Dr. Saverio Alberti is President of this company. This affiliation does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. A patent related to this work is “Anti-Trop-2 monoclonal antibodies and uses thereof in the treatment and diagnosis of tumors” – PCT/IT2009/000035.

                Conceived and designed the experiments: SA. Performed the experiments: VR PS MT RLS RL. Analyzed the data: PQ RL M. Pedriali FA MF PB EB M. Piantelli. Wrote the paper: FA EB SA. Managed the revision of the manuscript: MT.

                Article
                PONE-D-13-51525
                10.1371/journal.pone.0096993
                4019539
                24824621

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Pages: 11
                Funding
                This work was supported by the Fondazione of the Cassa di Risparmio della Provincia di Chieti, the EU NoE Biopattern (FP6-2002-IST-1 no. 508803), Oncoxx Biotech, Compagnia di San Paolo, the Italian Ministry of Health (RicOncol RF-EMR-2006-361866), and the Italian Association for Cancer Research (AIRC, Italy). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Histology
                Biochemistry
                Biomarkers
                Cell Biology
                Signal Transduction
                Cell Signaling
                Calcium Signaling
                Molecular Cell Biology
                Medicine and Health Sciences
                Diagnostic Medicine
                Epidemiology
                Cancer Epidemiology
                Oncology
                Cancers and Neoplasms
                Breast Tumors
                Pathology and Laboratory Medicine

                Uncategorized

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