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      MZB1 expression indicates poor prognosis in estrogen receptor-positive breast cancer

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          Abstract

          Breast cancer (BC) is the most common malignant tumor in females. Development of novel biomarkers or therapeutic targets may contribute toward the improvement of a patient's prognosis. Marginal zone B and B1 cell-specific protein (MZB1) is an unfolded protein response-related chaperone and mainly exists in the endoplasmic reticulum of B lymphocytes, although little is known regarding its role in BC cells. The present study aimed to investigate the significance of MZB1 expression in BC. To begin with, MZB1 mRNA expression levels in 13 BC cell lines and two non-cancerous mammary cell lines were evaluated. Next, mRNA and protein expression of MZB1 in BC patient tumor specimens was evaluated to assess the association between expression and clinicopathological factors or prognosis. MZB1 mRNA expression levels were detectable in four estrogen receptor (ER)-positive BC cell lines. When ratios of MZB1 mRNA expression levels between BC and non-cancerous specimens were evaluated, patients with stage III disease exhibited a higher ratio than patients with stage 0/I/II disease (P=0.009). Using immunohistochemistry, patients with ER-positive BC more frequently expressed MZB1, compared with patients with ER-negative BC (P=0.003). In patients with ER-positive BC, patients with MZB1-positive BC experienced shorter disease-free survival (DFS) times than patients with negative BC (P=0.026). Multivariate analysis of DFS demonstrated that MZB1 positivity was an independent prognostic factor (P=0.022). The results of the present study suggested that MZB1 expression may be associated with a more advanced stage of BC. Furthermore, in patients with ER-positive BC, MZB1 may be a potential prognostic marker.

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          Most cited references20

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          Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase.

          The transcription of genes encoding soluble proteins that reside in the endoplasmic reticulum (ER) is induced when unfolded proteins accumulate in the ER. Thus, an intracellular signal transduction pathway must exist that mediates communication between the ER lumen and the nucleus. We have identified a gene in S. cerevisiae, IRE1, that is required for this pathway: ire1- mutants cannot activate transcription of KAR2 and PDI1, which encode the ER resident proteins BiP and protein disulfide isomerase. Moreover, IRE1 is essential for cell viability under stress conditions that cause unfolded proteins to accumulate in the ER. IRE1 encodes a transmembrane serine/threonine kinase that we propose transmits the unfolded protein signal across the ER or inner nuclear membrane. IRE1 is also required for inositol prototrophy, suggesting that the induction of ER resident proteins is coupled to the biogenesis of new ER membrane.
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            The new TNM-based staging of breast cancer

            This review describes the changes that have been implemented in the Tumor-Node-Metastasis (TNM)-based staging of breast cancers by the new, 8th editions of the relevant Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) publications. After giving a background for TNM being the common language of cancer staging and related activities like cancer treatment and registration, it summarizes not only the changes but reviews some highlights important for pathologists, and lists and comments on the differences between the publications and diagnostic practices based on them. A section is dedicated to the prognostic stages of breast carcinomas introduced in the AJCC Cancer Staging Manual, but not mentioned in the UICC TNM classification of malignant tumors. A few issues that are not appropriately covered by TNM according to the authors' view (e.g., multifocal tumors, larger lymph node metastases identified by molecular methods, the heterogeneous prognosis of M1-defined stage IV disease) close the review with the final thoughts raising the vision of a potential loss of the common staging language.
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              Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions.

              The 78 kDa glucose-regulated stress protein GRP78 is induced by physiological stress conditions such as hypoxia, low pH, and glucose deprivation which often exist in the microenvironments of solid tumors. Activation of this stress pathway occurs in response to several pro-apoptotic stimuli. In vitro studies have demonstrated a correlation between induced expression of GRP78 and resistance to apoptotic death induced by topoisomerase II-directed drugs. We were interested in characterizing this protein in human breast lesions for potential implications in chemotherapeutic intervention. Surgical specimens of human breast lesions and paired normal tissues from the same patients were flash frozen for these studies. Total RNA and/or protein were extracted from these tissues and used in northern and/or western blot analyses, respectively, to quantify the relative expression of GRP78. Northern blot analysis indicated that 0/5 benign breast lesions, 3/5 estrogen receptor positive (ER+) breast tumors, and 6/9 estrogen receptor negative (ER-) breast tumors exhibited overexpression of GRP78 mRNA compared to paired normal tissues, with fold overexpressions ranging from 1.8 to 20. Western blot analyses correlated with these findings since 0/5 benign breast lesions, 4/6 ER+ breast tumors, and 3/3 ER- breast tumors overexpressed GRP78 protein with fold overexpressions ranging from 1.8 to 19. Immunohistochemical analysis of these tissues demonstrated that the expression of GRP78 was heterogeneous among the cells comprising different normal and malignant glands, but confirmed the overexpression of GRP78 in most of the more aggressive ER- tumors. These results suggest that some breast tumors exhibit adverse microenvironment conditions that induce the overexpression of specific stress genes that may play a role in resistance to apoptosis and decreased chemotherapeutic efficacy.
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                Author and article information

                Journal
                Oncol Lett
                Oncol Lett
                OL
                Oncology Letters
                D.A. Spandidos
                1792-1074
                1792-1082
                November 2020
                04 September 2020
                04 September 2020
                : 20
                : 5
                : 198
                Affiliations
                [1 ]Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
                [2 ]Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
                [3 ]Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
                Author notes
                Correspondence to: Dr Masahiro Shibata, Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan, E-mail: m-shibata@ 123456med.nagoya-u.ac.jp
                Article
                OL-0-0-12059
                10.3892/ol.2020.12059
                7491119
                32963604
                47dadf85-73d0-4c8e-b915-c9e57b5bdc1a
                Copyright: © Watanabe et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 26 March 2020
                : 18 August 2020
                Categories
                Articles

                Oncology & Radiotherapy
                breast cancer,mzb1,chaperone,er-positive,prognostic marker
                Oncology & Radiotherapy
                breast cancer, mzb1, chaperone, er-positive, prognostic marker

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