scholarly journals OCT1 Is a Poor Prognostic Factor for Breast Cancer Patients and Promotes Cell Proliferation via Inducing NCAPH

2021 ◽  
Vol 22 (21) ◽  
pp. 11505
Author(s):  
Takuya Ogura ◽  
Kotaro Azuma ◽  
Junichiro Sato ◽  
Keiichi Kinowaki ◽  
Ken-Ichi Takayama ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Prognostic Factor ◽  
Disease Free Survival ◽  
Breast Cancer Patients ◽  
Clinical Value ◽  
Poor Prognostic Factor ◽  
Er Positive ◽  
Mcf 7 ◽  
Positive Breast Cancer

Octamer transcription factor 1 (OCT1) is a transcriptional factor reported to be a poor prognostic factor in various cancers. However, the clinical value of OCT1 in breast cancer is not fully understood. In the present study, an immunohistochemical study of OCT1 protein was performed using estrogen receptor (ER)-positive breast cancer tissues from 108 patients. Positive OCT1 immunoreactivity (IR) was associated with the shorter disease-free survival (DFS) of patients (p = 0.019). Knockdown of OCT1 inhibited cell proliferation in MCF-7 breast cancer cells as well as its derivative long-term estrogen-deprived (LTED) cells. On the other hand, the overexpression of OCT1 promoted cell proliferation in MCF-7 cells. Using microarray analysis, we identified the non-structural maintenance of chromosomes condensin I complex subunit H (NCAPH) as a novel OCT1-taget gene in MCF-7 cells. Immunohistochemical analysis showed that NCAPH IR was significantly positively associated with OCT1 IR (p < 0.001) and that positive NCAPH IR was significantly related to the poor DFS rate of patients (p = 0.041). The knockdown of NCAPH inhibited cell proliferation in MCF-7 and LTED cells. These results demonstrate that OCT1 and its target gene NCAPH are poor prognostic factors and potential therapeutic targets for patients with ER-positive breast cancer.

scholarly journals Effect of Wnt5a on drug resistance in estrogen receptor-positive breast cancer

2020 ◽  
Author(s):  
Ai Amioka ◽  
Takayuki Kadoya ◽  
Satoshi Sueoka ◽  
Yoshie Kobayashi ◽  
Shinsuke Sasada ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Poor Prognosis ◽  
Breast Cancer Tissue ◽  
Cancer Tissue ◽  
Breast Cancer Patients ◽  
Mtor Signaling Pathway ◽  
The Poor ◽  
Er Positive ◽  
Mcf 7 ◽  
Positive Breast Cancer

Abstract BackgroundIt was previously reported by us that Wnt5a-positive breast cancer can be classified as estrogen receptor (ER)-positive breast cancer and its prognosis is worse than that of Wnt5a-negative breast cancer. Herein, the molecular mechanisms underlying the poor prognosis of Wnt5a-positive breast cancer patients were examined. MethodsA total of 151 consecutive ER-positive breast cancer patients who underwent resection between January 2011 and February 2014 were enrolled. DNA microarray and pathway analyses were performed conducted using MCF-7 cells stably expressing Wnt5a (MCF-7/Wnt5a(+)). Based on the results, cell viability and drug sensitivity assays as well as mutation analysis , were performed using culture cells and breast cancer tissue. The relationship between Wnt5a and the PI3K–AKT–mTOR signaling pathway was examined.ResultsThe relapse-free survival rate in patients with Wnt5a-positive breast cancer was significantly lower than that in patients with Wnt5a-negative breast cancer ( P = 0.047). DNA microarray data indicated that only the cytochrome P450 (CYP) pathway was significantly upregulated in MCF-7/Wnt5a(+) cells ( P = 0.0440). MCF-7/Wnt5a(+) cells showed reduced sensitivity to the metabolic substrates of CYP, tamoxifen ( P < 0.001), and paclitaxel ( P < 0.001). PIK3CA mutations were unrelated to Wnt5a expression in breast cancer tissue and culture cells.ConclusionsIn ER-positive breast cancer, Wnt5a upregulated the CYP metabolic pathway; additionally, it inhibited the sensitivity to tamoxifen and paclitaxel, which constitute the standard treatment options for ER-positive breast cancer. Wnt5a could be involved in the poor prognosis of ER-positive breast cancer independently of the PI3K–AKT–mTOR signaling pathway.

scholarly journals miR-200 affects tamoxifen resistance in breast cancer cells through regulation of MYB

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yu Gao ◽  
Wenzhi Zhang ◽  
Chengwen Liu ◽  
Guanghua Li
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tamoxifen Resistance ◽  
Breast Cancer Patients ◽  
Over Expression ◽  
Er Positive ◽  
Emt Markers ◽  
Mcf 7 ◽  
Positive Breast Cancer

AbstractResistance to tamoxifen is a major clinical challenge. Research in recent years has identified epigenetic changes as mediated by dysregulated miRNAs that can possibly play a role in resistance to tamoxifen in breast cancer patients expressing estrogen receptor (ER). We report here elevated levels of EMT markers (vimentin and ZEB1/2) and reduced levels of EMT-regulating miR-200 (miR-200b and miR-200c) in ER-positive breast cancer cells, MCF-7, that were resistant to tamoxifen, in contrast with the naïve parental MCF-7 cells that were sensitive to tamoxifen. Further, we established regulation of c-MYB by miR-200 in our experimental model. C-MYB was up-regulated in tamoxifen resistant cells and its silencing significantly decreased resistance to tamoxifen and the EMT markers. Forced over-expression of miR-200b/c reduced c-MYB whereas reduced expression of miR-200b/c resulted in increased c-MYB We further confirmed the results in other ER-positive breast cancer cells T47D cells where forced over-expression of c-MYB resulted in induction of EMT and significantly increased resistance to tamoxifen. Thus, we identify a novel mechanism of tamoxifen resistance in breast tumor microenvironment that involves miR-200-MYB signaling.

Sequential versus concurrent use of chemotherapy and endocrine therapy in the adjuvant treatment of ER-positive breast cancer: A systematic review and Bayesian network meta-analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12040-e12040
Author(s):  
Tianfu Li ◽  
Zhen Shan ◽  
Liang Yu ◽  
Xiaying Kuang ◽  
Deyuan Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Adjuvant Treatment ◽  
Randomized Clinical Trials ◽  
Statistical Significance ◽  
Disease Free Survival ◽  
Breast Cancer Patients ◽  
Concurrent Use ◽  
Er Positive ◽  
Positive Breast Cancer

e12040 Background: Chemotherapy followed by endocrine therapy is the standard adjuvant treatment strategy for estrogen receptor-positive breast cancer patients. However, no direct evidence so far demonstrated better efficacy of sequential use of chemotherapy and endocrine therapy over concurrent. Objective: To evaluate the efficacy between sequential and concurrent use of chemotherapy and endocrine therapy in the adjuvant treatment of ER positive breast cancer. Methods: Randomized clinical trials comparing chemotherapy and/or endocrine therapy in the adjuvant treatment of ER positive breast cancer were included. Hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS) were extracted and analyzed in Bayesian analysis. Patients were stratified by menopause status for subgroup analysis. Results: 37 trials were identified with 37225 patients enrolled in total, 37 trials with DFS results and 24 with OS. 3 comparisons were done between sequential and concurrent arms. In DFS analysis, no statistical significance was found in all 3 comparisons [CHE seq/con TAM (HR 1.01, 95%CI 0.8497 - 1.199); CHE seq/con OFS+TAM (HR 0.9119, 95%CI 0.5666 - 1.49); CHE seq/con OFS+AI (HR 1.032, 95%CI 0.6291 - 1.776)]. The same were seen in OS analysis [CHE seq/con TAM (HR 0.9512, 95%CI 0.8053 - 1.125); CHE seq/con OFS+TAM (HR 1.065, 95%CI 0.6344 - 1.789); CHE seq/con OFS+AI (HR 1.069, 95%CI 0.665 - 1.717)]. Rankings were done for preferable treatment recommendations. In DFS analyses, sequential arms ranked higher than concurrent arms [CHE seq/con OFS+AI (1 vs. 3); CHE seq/con OFS+TAM (6 vs. 7); CHE seq/con TAM (8 vs. 8)]. The same tendency was seen in OS analyses [CHE seq/con OFS+AI (1 vs. 2); CHE seq/con TAM (4 vs. 5)] except for CHE seq/con OFS+TAM (11 vs. 6-9). In subgroup ranking results, CHE seq/con OFS+AI and CHE seq/con OFS+TAM showed consistency among comparisons with concurrent arms ranked higher than sequential arms. However, CHE seq TAM ranked higher than CHE con TAM in all comparisons. Conclusions: The combination of chemotherapy and endocrine therapy in the adjuvant treatment of ER positive breast cancer demonstrated equal efficacy either used sequentially or concurrently. However, concurrent arms were recommended over sequential arms in premenopausal patients for better DFS and OS, except for the combination of chemotherapy and tamoxifen which was recommended to be used sequentially. Others: This study has been registered in PROSPERO (CRD42018104889).

scholarly journals Oxysterol signalling is retained in ER-negative and supressed in ER-positive breast cancer

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Samantha Hutchinson ◽  
Sebastiano Battaglia ◽  
Hanne Roberg-Larsen ◽  
Priscilia Lianto ◽  
Thomas Hughes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Tissue Bank ◽  
Disease Free Survival ◽  
Luciferase Reporter ◽  
Receptor Alpha ◽  
Increased Risk ◽  
Er Positive ◽  
Mcf 7 ◽  
Positive Breast Cancer

AbstractBreast cancer treatment and prognosis is informed by biomarker expression. Expression of Oestrogen Receptor-alpha (ERα) for example influences whether the patient receives endocrine- or chemo-therapy. Nutritional status is a modifier of disease free survival and elevated circulating cholesterol associates with increased risk of relapse. Cholesterol hydroxylation produces ‘oxysterols’ which are selective Liver X Receptor alpha (LXRα) modulators and ERα agonists. In ER-positive breast cancer, oxysterols induce proliferation and resistance to endocrine therapy, whilst in ER-negative disease oxysterols are anti-proliferative and pro-metastatic suggesting that there are breast cancer subtype specific differences in the genomic targets of the oxysterol-LXR pathway. This study explored the regulation of LXRα signalling in ER-positive and ER-negative breast cancer, and how ligand, receptor and co-factors combine to regulate LXRα target gene expression in different breast cancer types.In vitro, MDA.MB.468 (ER-negative) cells were more responsive than MCF-7 (ER-positive) cells to synthetic LXRα agonists (T0901317, GW3965) and six oxysterols (22-hydroxycholesterol [22-OHC], 24-OHC, 25-OHC, 27-OHC, 7-ketocholesterol and 24,25-epoxycholesterol), as measured by MTT, LXR-luciferase reporter, and qPCR of canonical targets ABCA1 and APOE (Students t-tests: p < 0.01). Responses to the antagonist GSK2033 was comparable across cell lines. In vivo, LXRa expression correlated with 48/146 target genes in ER-negative (n = 81), but with just 9/146 in ER-positive tumours (n = 234) (Fischer exact test: p < 0.0001) indicating greater LXRa-mediated transcription of target genes in the aggressive subtype. This was not explained by ligand concentration, as we developed a novel fast oxysterol detection system and found no difference in concentration of 22-OHC, 24-OHC, 25-OHC or 27-OHC between ER-negative (n = 11) and ER-positive (n = 11) primary tumours obtained from the Leeds Breast Tissue Bank. However, we did observe that expression of LXRa and 2/7 of its co-activators (SRC, TRRAP) were higher in ER-negative relative to ER-positive disease (using TCGA data from cBioPortal) (Mann-Whitney U test: p < 0.001), and that expression of all LXRa co-repressors were lowest in ER-negative disease (NCOR1, NCOR2, LCOR: Mann-Whitney U test: p < 0.001 for all). siRNA knock-down of NCOR1 and NCOR2 resulted in MCF-7 cells that mimicked the response of MDA.MB.468 cells to oxysterols (as measured by LXR-luciferase and qPCR assay).These data indicate that despite the anti-proliferative actions of oxysterol-LXRa signalling, there is a, yet to be identified, selective advantage for retention and enhancement of this pathway in ER-negative breast cancer. Dietary routes to selective LXRa modulation (such as plant sterols) may provide patient-led routes to improving ER-negative survival rates.

scholarly journals Paeoniflorin Enhances the Sensitivity of ER-Positive Breast Cancer Cells to Tamoxifen through Promoting Sirtuin 4

2022 ◽  
Vol 2022 ◽  
pp. 1-11
Author(s):  
Pei Zhang ◽  
Nan Wu ◽  
Zhi-Jun Song ◽  
Zheng-Fu Tai
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Protein Expression ◽  
Cancer Cells ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Expression Ratio ◽  
Er Positive ◽  
Mcf 7 ◽  
Positive Breast Cancer

Tamoxifen is an effective drug for treating patients with advanced estrogen receptor-positive (ER+) breast cancer (BC), but not for all ER + BC patients. Drug tolerance is the biggest obstacle. In this study, we designed an experiment to investigate whether paeoniflorin affects the ER + BC cell’s sensitivity to tamoxifen in the T47D and MCF-7 cell lines. Herein, we found that paeoniflorin inhibited cell proliferation without inducing apoptosis. However, it enhanced tamoxifen-induced apoptosis in both cell lines. Immunoblotting revealed that paeoniflorin significantly increased the already elevated Bax/Bcl2 protein expression ratio and the caspase 3 activity levels, both induced by tamoxifen. Paeoniflorin was also found to increase SIRT4 expression, and deletion of SIRT4 could significantly reverse the inhibition of cell proliferation induced by paeoniflorin and significantly decrease paeoniflorin-enhanced apoptosis induced by tamoxifen. Moreover, protein expression detection revealed that paeoniflorin enhanced the tamoxifen-induced inhibition of STAT3 activation. Besides, the deletion of SIRT4 could significantly increase STAT3 activation in the T47D and MCF-7 cells. In conclusion, paeoniflorin suppressed STAT3 activation to enhance the sensitivity of ER-positive breast cancer cells to tamoxifen through promoting SIRT4 expression.

Low expression of microRNA-195 is a poor prognostic marker for ER-positive breast cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12576-e12576
Author(s):  
Yoshihisa Tokumaru ◽  
Masanori Oshi ◽  
Eriko Katsuta ◽  
Vijayashree Murthy ◽  
Nobuhisa Matsuhashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Poor Survival ◽  
Er Positive ◽  
Small Cohort ◽  
Low Expression ◽  
Positive Breast Cancer

e12576 Background: MicroRNA-195 (miR-195) is a tumor suppressive microRNA in breast cancer; however, its clinical relevance remains debatable because most data is either in vitro or from small cohort studies. In this study, we hypothesized that miR-195 low expressing tumors associate with high proliferative characteristics and poor survival. Methods: We obtained the clinical data and survival information of breast cancer patients from two large publicly available databases and one small cohort; The Cancer Genome Atlas (TCGA),The Molecular Taxonomy of Breast Cancer International Consortium (METARBRIC), and GSE45666. Total of 755, 1287, and 116 patients’ data were obtained from TCGA, METABRIC, and GSE45666 respectively. Survival analysis, Overall survival (OS) and Disease-free survival (DFS) was performed by comparing the high and low expression groups. CYT score, xCell, and other immunological factors were used to evaluate intratumoral immune cell composition. Also, gene set enrichment analysis (GSEA) was performed between miR-195 high and low expression groups. Results: The patients were divided into miR-195 high and low groups by utilizing median cutoff. At first, we confirmed that miR-195 expression was significantly lower in tumors compared to normal breast tissue in TCGA as well as GSE45666. Advanced grades were significantly associated with lower expression of miR-195 in ER positive/HER2 negative (ER+/HER2) subtype with both TCGA and METABRIC cohorts ( p< 0.001 and p< 0.001, respectively). On the contrary this was not consistent with other subtypes, HER2+ and triple negative (TN). Also, Low miR-195 expressing tumors demonstrated higher MKI67 expressions in ER+/HER2- subtype with TCGA ( p< 0.001). This was validated with METABRIC cohort ( p< 0.001). Furthermore, GSEA demonstrated that low miR-195 expressing tumors enriched the gene sets related with cell cycle or cell proliferation, such as MYC signaling, mTOR signaling, E2F signaling, G2M Checkpoint signaling and PI3K_Akt_mTOR signaling, compared with high miR-195 expressing tumors in ER+/HER2-. Conclusions: Low expression of miR-195 was associated with improved OS in ER positive breast cancer patients. Also, low miR-195 expressing tumors were found to associate with advanced grades as well as enriching the genes relating to cell proliferation and cell cycle, which may explain the poor survival of low miR-195 expressing patients in ER positive breast cancer.

scholarly journals miR-221/222 sponge abrogates tamoxifen resistance in ER-positive breast cancer cells through restoring the expression of ERα

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Yan Xiu Ouyang ◽  
Jun Feng ◽  
Zun Wang ◽  
Guo Jun Zhang ◽  
Min Chen
Keyword(s):  
Breast Cancer ◽  
Tamoxifen Resistance ◽  
Cancer Cell Line ◽  
Breast Cancer Patients ◽  
Cmv Promoter ◽  
Pulldown Assay ◽  
Er Positive ◽  
Resistant Breast Cancer Cell ◽  
Mcf 7 ◽  
Positive Breast Cancer

AbstractTamoxifen resistance (TamR) prevents ER-positive breast cancer patients from benefitting from endocrine therapy, and miR-221 or miR-222 plays vital roles in inducing TamR. In this study, we designed synthetic sponges to reverse TamR by targeting these two miRs. First, we established a tamoxifen resistant breast cancer cell line (MCF-7TamR), we verified the high expressing level of these two miRs in TamR cells. miR-221 or miR-222 inhibitors rendered MCF-7TamR cells responsive to tamoxifen. Next, we designed a miR-221/222 sponge, which contains total 8 multi-antisense binding sites (MBSs) for these two onco-miRs, and inserted it into CMV promoter- or hTERT promoter-driven expressing vectors. After transfected miR-221/222 sponge expressing vectors into MCF-7TamR cells, we identified a strong interaction between miR-221/222 sponge and endogenous miR-221 or miR-222 by RNA pulldown assay. We also found that miR-221/222 sponge restored the expression of ERα and PTEN, arrested cells in G1 phase, and finally resulted in reduced cell growth and cell migration. Notably, miR-221/222 sponge expressing cells abrogates tamoxifen resistance through restoring the expression of ERα, suggesting that miR-221/222 sponge gene therapy especially driven by tumor specific promoter could provide an effective therapeutic approach against TamR in breast cancer.

Sign in / Sign up

Export Citation Format

Share Document