Browsing by Subject "Estrogen receptor alpha"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Open Access Alteration in the subcellular location of the inhibitor of growth protein p33(ING1b) in estrogen receptor alpha positive breast carcinoma cells(Scientific and Technical Research Council of Turkey, 2017) Kunter, İ.; Kandemiş, E.; Alotaibi, Hani; Canda, T.; Bağrıyanık, E. E.ING1 has regulatory roles in the expression of genes associated with proliferation, apoptosis, and senescence. p33(ING1b) is the most widely expressed isoform of the gene. Downregulation of its nuclear expression is involved in differentiation and pathogenesis in invasive breast carcinoma. Yet the mechanism(s) by which p33 nuclear targeting is regulated remains unknown. In this study, we analyzed human invasive breast carcinoma tissue samples by immunostaining with p33 and correlating p33 location with the presence of ERα. Our findings show the expression of p33 protein in ERα-positive tumor samples was in the nucleus alone, while the expression was mainly in the cytoplasm in ERα-negative tumor samples. Examination of the localization of p33 in the nucleus and/or cytoplasm in several different cell lines demonstrated 17β-estradiol (E2) treatment causes dramatic compartmental shift in p33 protein from the cytoplasm to the nucleus in ERα-positive MDA-66 cells. No significant differences in ERα-negative MDA-MB-231 cells in the same conditions were observed. We show for the first time nuclear localization of p33 is regulated by estradiol induction in ERα-positive breast cancer cells. These results suggest compartmental shift in p33 by ER signaling may be an important molecular event in the differentiation and pathogenesis of invasive breast cancer. © TÜBİTAK.Item Open Access MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer(John Wiley and Sons Ltd, 2014) Ward, A.; Shukla, K.; Balwierz, A.; Soons, Z.; König, R.; Sahin, O.; Wiemann, S.Tamoxifen is an endocrine therapy which is administered to up to 70% of all breast cancer patients with oestrogen receptor alpha (ERα) expression. Despite the initial response, most patients eventually acquire resistance to the drug. MicroRNAs (miRNAs) are a class of small non-coding RNAs which have the ability to post-transcriptionally regulate genes. Although the role of a few miRNAs has been described in tamoxifen resistance at the single gene/target level, little is known about how concerted actions of miRNAs targeting biological networks contribute to resistance. Here we identified the miRNA cluster, C19MC, which harbours around 50 mature miRNAs, to be up-regulated in resistant cells, with miRNA-519a being the most highly up-regulated. We could demonstrate that miRNA-519a regulates tamoxifen resistance using gain- and loss-of-function testing. By combining functional enrichment analysis and prediction algorithms, we identified three central tumour-suppressor genes (TSGs) in PI3K signalling and the cell cycle network as direct target genes of miR-519a. Combined expression of these target genes correlated with disease-specific survival in a cohort of tamoxifen-treated patients. We identified miRNA-519a as a novel oncomir in ER+ breast cancer cells as it increased cell viability and cell cycle progression as well as resistance to tamoxifen-induced apoptosis. Finally, we could show that elevated miRNA-519a levels were inversely correlated with the target genes' expression and that higher expression of this miRNA correlated with poorer survival in ER+ breast cancer patients. Hence we have identified miRNA-519a as a novel oncomir, co-regulating a network of TSGs in breast cancer and conferring resistance to tamoxifen. Using inhibitors of such miRNAs may serve as a novel therapeutic approach to combat resistance to therapy as well as proliferation and evasion of apoptosis in breast cancer.