Reduction of nuclear Y654-p-p-catenin expression through SH3GL2-meditated downregulation of EGFR in chemotolerance TNBC: Clinical and prognostic importance

Saimul Islam; Hemantika Dasgupta; Mukta BasuAnup RoyNeyaz AlamSusanta RoychoudhuryChinmay Kumar Pa

摘要

Triple negative breast cancer (TNBC) originates from a less differentiated ductal cell of breast, which is less sensitive to chemotherapy. The chemotolerance mechanism of TNBC has not yet been studied in detail. For this reason, molecular profiles (expression/genetic/epigenetic) of Y654-p-β-catenin (active) and its kinase epidermal growth factor receptor (EGFR) along with SH3GL2 (regulator of EGFR homeostasis) were compared between neoadjuvant chemotherapy treated (NACT) and pretherapeutic TNBC samples. Reduced nuclear expression of Y654-p-β-catenin protein with low proliferation index and CD44 prevalence showed concordance with reduced expression of EGFR/Y1045-p-EGFR proteins in the NACT samples than the pretherapeutic TNBC samples. Infrequent messenger RNA expression, gene amplification (10-32.5%), and mutation (1%) of EGFR were seen in the TNBC samples irrespective of therapy, suggesting the importance of EGFR protein stabilization in this tumor. The upregulation of SH3GL2 seen in the NACT samples in contrast to the pretherapeutic samples might be due to its promoter hypomethylation, as seen in the quantitative methylation assay. A similar trend of upregulation of SH3GL2 and downregulation of EGFR, Y1045-p-EGFR, Y654-p-β-catenin were seen in the MDA-MB-231 cell line using antharacycline antitumor drugs (doxorubicin/nogalamycin). The NACT patients with reduced expression of Y654-p-β-catenin and/or EGFR and high expression of SH3GL2 showed comparatively better prognosis than the pretherapeutic patients. Thus, our study showed that reduced nuclear expression of Y654-p-β-catenin in NACT samples due to downregulation of EGFR protein through promoter hypomethylation-mediated upregulation of SH3GL2, resulting in low proliferation index/CD44 prevalence with better prognosis of the NACT patients, might have an important role in the chemotolerance of TNBC.

机译：三阴乳腺癌(TNBC)产生从一个不分化的乳腺导管细胞,这是对化疗不敏感。chemotolerance TNBC尚未机制详细研究了。配置文件(表达式/基因表观遗传)Y654-p -β连环蛋白(活动)及其激酶表皮生长因子受体(EGFR)与SH3GL2(表皮生长因子受体体内平衡的调节器)对比新辅助化疗治疗(NACT)和pretherapeutic TNBC样本。核表达Y654-p -β连环蛋白的蛋白质较低的扩散指数和CD44患病率显示一致的表达减少表皮生长因子受体/ Y1045-p-EGFR蛋白质NACT样本比pretherapeutic TNBC样本。信使RNA表达,基因扩增(10 - 32.5%)和表皮生长因子受体突变(1%)TNBC的样品无论治疗,表明EGFR蛋白的重要性稳定的肿瘤。SH3GL2 NACT样品相比pretherapeutic样本可能由于它启动子hypomethylation,如见甲基化定量分析。的差别upregulation SH3GL2和对这些表皮生长因子受体、Y1045-p-EGFR Y654-p -β连环蛋白中看到mda - mb - 231细胞系使用antharacycline抗肿瘤药物阿霉素/诺加霉素)。NACT患者减少的表达Y654-p -β连环蛋白和/或EGFR高表达SH3GL2显示相对更好的预后比pretherapeutic病人。表明,减少核的表达由于在NACT Y654-p -β连环蛋白样品通过启动子downregulation EGFR蛋白hypomethylation-mediated upregulation SH3GL2,导致较低的扩散指数/ CD44患病率NACT有更好的预后患者,可能有一个重要的角色chemotolerance TNBC。

Reduction of nuclear Y654-p-p-catenin expression through SH3GL2-meditated downregulation of EGFR in chemotolerance TNBC: Clinical and prognostic importance

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