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      Expression of estrogen receptors and androgen receptor and their clinical significance in gastric cancer

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          Abstract

          Despite the mounting studies exploring the role of estrogen receptor alpha (ERα), estrogen receptor beta (ERβ) and androgen receptor (AR) in gastric cancer (GC), there remain controversies in those findings. The present study investigated the expression of ERα, ERβ and AR in Chinese gastric cancer by immunohistochemistry, analyzed their clinical relevance in gastric cancer, and examined the potential mechanisms by which ERα and AR modulated GC progression. The positive rate of ERα, ERβ and AR in GC tissues was 6% (9/150), 93.5% (143/153), and 42.4% (59/139), respectively. The expression of ERα was an independent unfavorable risk factor for overall survival (OS) (hazard ratio [HR] = 3.639, 95% confidence interval [CI] = 1.432-9.246, p = 0.007) for GC patients. Moreover, AR was borderline significantly associated with poor progress free survival (PFS) after adjustment with other variables (HR = 1.573, 95% CI = 0.955-2.592, p = 0.075). Knockdown of ERα inhibited the proliferation, migration and invasion of GC cells possibly via modulating the expression of p53, p21, p27, cyclin D1 and E-cadherin. Downregulation of AR suppressed the migration and invasion of GC cells and inhibited the epithelial-mesenchymal transition (EMT) associated pathways.

          Conclusion

          The present study showed that positive ERα was associated with poor prognosis of Chinese GC patients. ERα might modulate the proliferation, migration and invasion via regulating the expression of p53, p21, p27, cyclin D1 and E-cadherin. ERα could be a valuable prognostic biomarker and promising therapeutic target for Chinese GC patients.

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          Most cited references25

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          Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer.

          The p53 (also known as TP53) tumor suppressor gene encodes for a nuclear phosphoprotein thought to regulate proliferation of normal cells. Most p53 mutations result in a nonfunctional protein that accumulates in tumor cell nuclei. These common mutations appear to be involved in the development and/or progression of several neoplastic diseases including human breast cancer. Our purpose was to investigate the relationships between levels of mutant p53 protein expression, tumor cell proliferation rate, and clinical outcome in patients with node-negative breast cancer. Expression of mutant p53 protein was evaluated by frozen-section immunohistochemistry (IHC) and light microscopy in 700 breast cancers from axillary lymph node-negative patients with long-term follow-up (median, 54 months). The immunostaining signal was expressed as the sum of scores representing the proportion and staining intensity of negative and positive tumor cell nuclei (ranges, 0 and 2-8, respectively). Statistical comparisons were made between levels of p53 protein expression and disease-free survival, overall survival, and tumor proliferation rate expressed as the percentage of cells in the S phase (%S phase) as determined by flow cytometry. Of the 700 tumors, 362 (52%) showed positive nuclear immunostaining (IHC score > 0). Proliferation rates were significantly higher (P = .0001) in positive tumors (median %S phase, 7.1%) than in negative tumors (4.1%). In a univariate cutpoint analysis, negative tumors (n = 388) versus low-positive tumors (IHC score = 2-6; n = 263) versus high-positive tumors (IHC score > 6; n = 99) showed progressively reduced disease-free survival (80% versus 72% versus 58% at 5 years, respectively; P < or = .05 for all pairwise comparisons). Analogous results for overall survival were 88% versus 84% versus 74%; only the result for negative versus high positive tumors was significant (P = .003). In a multivariate analysis, expression of p53 protein and high %S phase were independently associated with reduced disease-free survival (P = .008 and .01, respectively). Expression of mutant p53 protein was associated with high tumor proliferation rate, early disease recurrence, and early death in node-negative breast cancer. Despite the strong direct correlation between accumulation of p53 protein and tumor proliferation rate, both factors were independently associated with poor prognosis, suggesting that p53 may have other biological functions in addition to cell-cycle regulation. This test, when combined with other prognostic factors, may enhance our ability to identify node-negative breast cancer patients at high risk for early disease recurrence and/or death, for whom the use of adjuvant chemotherapy is unequivocally justified.
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            Oestrogen and the enigmatic male predominance of gastric cancer.

            Gastric cancer is the second most common cause of cancer death worldwide, and annually it causes over 150,000 deaths in Europe and 700,000 deaths globally. The incidence of gastric cancer shows an enigmatic male dominance with a male-to-female ratio of about 2:1. This sex ratio cannot be entirely attributed to the differences in the prevalence of known risk factors between the sexes. This review focuses on the potential role of oestrogen in explaining the male predominance in gastric cancer. Some data argue in favour of sex hormonal influence. Women with a longer fertility life and those on hormone replacement therapy seem to have a decreased risk of gastric cancer, and men who have been treated with oestrogen for prostate cancer have a decreased risk. Use of tamoxifen in women seems to increase their risk of gastric cancer. Animal studies indicate that oestrogen may offer protection against the development of this cancer as for example ovariectomised mice are at an increased risk, whilst administration of female sex hormones decreases the incidence of gastric cancer. Oestrogen may exert its effect by acting on oestrogen receptors (ERs). Both ERalpha, ERbeta and the latest discovered ERbetacx have been identified in gastric tissue. The biological means behind this is not yet clear but various mechanisms have been suggested. There are indications that oestrogen may lead to an increased expression of trefoil factor proteins, which protect mucous epithelia or inhibit the expression of c-erb-2 oncogene.
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              Estrogen receptor and breast cancer.

              Breast cancer, the most common malignancy in women, was already known to be associated with the steroid hormone estrogen more than a century ago. The discovery of the estrogen receptor (ER) provided us not only with a powerful predictive and prognostic marker, but also an efficient target for the treatment of hormone-dependent breast cancer with antiestrogens. In this paper we will sketch the important role of ER in the development, progression, and treatment of the disease, which is complicated by the receptor's interaction with co-regulatory proteins, its cross-talk with other signal transduction pathways, and its involvement in the development of antiestrogen resistance. Copyright 2001 Academic Press.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                20 June 2017
                28 March 2017
                : 8
                : 25
                : 40765-40777
                Affiliations
                1 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China
                2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
                3 Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
                4 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, P.R. China
                5 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China
                6 Department of Breast Surgery, Lanzhou General Hospital, Lanzhou, P.R. China
                Author notes
                Correspondence to: Zhe Zhang, zhangzhe2010fduscc@ 123456gmail.com
                Article
                16582
                10.18632/oncotarget.16582
                5522298
                28388558
                2ff55bf5-ec26-4515-b232-2d86f02998f5
                Copyright: © 2017 Tang et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 4 April 2016
                : 13 March 2017
                Categories
                Research Paper

                Oncology & Radiotherapy
                gastric cancer,estrogen receptor,androgen receptor,epithelial-mesenchymal transition

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