Analyse the differently expressed genes in tamoxifen resistant breast cancer cells
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PROVIDER: PRJNA438585 | ENA |
REPOSITORIES: ENA
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Project description:Tamoxifen resistance has been a major clinical problem and is accountable for relapse in about one third of ER positive breast cancer patients. Most of the recurrent patients will eventually receive chemotherapy. However, the chemosensitivity of these tamoxifen-resistant breast cancer patients has never been explored. In this study, we demonstrate that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, which results in the resistance to DNA-damaging chemotherapy including cisplatin and adriamycin , but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restored the sensitivity to cisplatin in tamoxifen-resistant cells. In addition, we identified that activated PI3K/AKT pathway in tamoxifen-resistant cells was responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors, BKM120 and BYL719, decreased the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitized them to cisplatin both in vitro and in xenografted mice. Higher BARD1 and BRCA1 expression was associated with poor prognosis of early breast cancer patients, especially the ones received radiotherapy, indicating the potential use of PI3K inhibitors to reverse chemoresistance and radioresistance in ER positive breast cancer patients.
2021-03-15 | GSE111926 | GEO
Project description:Tamoxifen is the most widely administered adjuvant first-line hormone therapy for Estrogen receptor α (ERα) positive breast cancer patients. However, one from three patients will develop resistance, while the underlying molecular mechanisms are currently unclear. Recent studies reported that abnormal expression of miRNAs played a role in cancer progress. To study the potential function of miRNAs in tamoxifen resistance, Affymetrix GeneChip® miRNA 3.0 microarray was employed to identify differentially expressed miRNAs between tamoxifen sensitive MCF7 parent (MCF7-Pa) cells and induced resistant (MCF7-Re) cells.
2015-03-07 | GSE66607 | GEO
Project description:Tamoxifen, an antagonist to estrogen receptor (ER), is a first line drug used in breast cancer treatment. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying the resistance to tamoxifen, we established a tamoxifen-resistant cell line by treating the MCF7 breast cancer cell line with tamoxifen for over 6 months. We showed that this cell line exhibited resistance to tamoxifen both in vitro and in vivo. In order to quantify the phosphorylation alterations associated with tamoxifen resistance, we performed SILAC-based quantitative phosphoproteomic profiling on the resistant and vehicle-treated sensitive cell lines where we identified >5,600 unique phosphopeptides. We found phosphorylation levels of 1,529 peptides were increased (>2 fold) and 409 peptides were decreased (<0.5-fold) in tamoxifen resistant cells compared to tamoxifen sensitive cells. Gene set enrichment analysis revealed that focal adhesion pathway was the top enriched signaling pathway activated in tamoxifen resistant cells. We observed hyperphosphorylation of the focal adhesion kinases FAK1 and FAK2 in the tamoxifen resistant cells. Of note, FAK2 was not only hyperphosphorylated but also transcriptionally upregulated in tamoxifen resistant cells. Suppression of FAK2 by specific siRNA knockdown could sensitize the resistant cells to the treatment of tamoxifen. We further showed that inhibiting FAK activity using the small molecule inhibitor PF562271 repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 significantly associated with short metastasis-free survival of ER-positive breast cancer patients treated with tamoxifen-based hormone therapy. Our studies suggest that FAK2 is a great potential target for the development of therapy for the treatment of hormone refractory breast cancers.
2016-05-25 | PXD001812 | Pride
Project description:Despite the availability of effective drugs that target ERα-positive breast cancer, resistance commonly occurs, resulting in relapse, metastasis, and death. Tamoxifen remains the most commonly-prescribed endocrine therapy worldwide, and “tamoxifen resistance” has been extensively studied. However, little consideration has been given to the role of tamoxifen’s primary active metabolite, endoxifen, in driving resistance mechanisms. Endoxifen is the most abundant active tamoxifen metabolite detected in patients and functions differently from the parent drug and other primary metabolites, including 4-hydroxy-tamoxifen (4HT). Many studies have shown that patients who extensively metabolize tamoxifen into endoxifen have superior outcomes relative to patients who do not, further supporting a primary role for endoxifen in driving tamoxifen responses. Therefore, “tamoxifen resistance” may be actually better modeled by “endoxifen resistance” for such patients. Here, we report the development of a novel endoxifen-resistant breast cancer cell line and have extensively compared this model to tamoxifen (4HT) and fulvestrant (ICI) resistant models. Endoxifen-resistant cells were found to be phenotypically and molecularly distinct from 4HT-resistant cells and more closely resembled ICI-resistant cells overall. Specifically, endoxifen resistance was associated with ERα and PR loss, estrogen insensitivity, EMT-like features, a unique gene signature, and striking resistance to most FDA-approved second- and third-line therapies. Given these findings, and the importance of endoxifen in the efficacy of tamoxifen therapy, our data indicate that endoxifen-resistant models may be more clinically relevant than existing models and suggest that a better understanding of endoxifen resistance could substantially improve patient care.
2021-01-11 | GSE164529 | GEO
Project description:A functional genetic screen to identify genes causing tamoxifen resistance in an estrogen-dependent human breast cancer cell model was performed. By insertion of defective retrovirus into the genome, individual genetic changes were introduced at random in ZR-75-1 cells. Subsequently, infected cells were selected for their ability to proliferate while being exposed to tamoxifen, and from these cultures stable cell lines were established. The retrovirus insertion sites were mapped enabling the identification of several candidate breast cancer anti-estrogen resistance (BCAR) genes. By cDNA transfection of estrogen-dependent cells resulting in their transformation into a tamoxifen-resistant phenotype, proof was provided for the causative role of BCAR genes.A functional genetic screen to identify genes causing tamoxifen resistance in an estrogen-dependent human breast cancer cell model was performed. By insertion of defective retrovirus into the genome, individual genetic changes were introduced at random in ZR-75-1 cells. Subsequently, infected cells were selected for their ability to proliferate while being exposed to tamoxifen, and from these cultures stable cell lines were established. The retrovirus insertion sites were mapped enabling the identification of several candidate breast cancer anti-estrogen resistance (BCAR) genes identified. By cDNA transfection of estrogen-dependent cells resulting in their transformation into a tamoxifen-resistant phenotype, proof was provided for the causative role of BCAR genes (Van Agthoven et al, Breast Cancer Res Treat DOI:10.1007/s10549-008-9969-5, 2008). To elucidate the mechanisms how these individual BCAR genes induce cell proliferation in growth-arrested ZR-75-1 cells, we assessed the gene expression patterns between the different groups of cell lines. Keywords: Expression profiling, reference design
2009-12-10 | GSE14513 | GEO
Project description:A functional genetic screen to identify genes causing tamoxifen resistance in an estrogen-dependent human breast cancer cell model was performed. By insertion of defective retrovirus into the genome, individual genetic changes were introduced at random in ZR-75-1 cells. Subsequently, infected cells were selected for their ability to proliferate while being exposed to tamoxifen, and from these cultures stable cell lines were established. The retrovirus insertion sites were mapped enabling the identification of several candidate breast cancer anti-estrogen resistance (BCAR) genes. By cDNA transfection of estrogen-dependent cells resulting in their transformation into a tamoxifen-resistant phenotype, proof was provided for the causative role of BCAR genes.A functional genetic screen to identify genes causing tamoxifen resistance in an estrogen-dependent human breast cancer cell model was performed. By insertion of defective retrovirus into the genome, individual genetic changes were introduced at random in ZR-75-1 cells. Subsequently, infected cells were selected for their ability to proliferate while being exposed to tamoxifen, and from these cultures stable cell lines were established. The retrovirus insertion sites were mapped enabling the identification of several candidate breast cancer anti-estrogen resistance (BCAR) genes identified. By cDNA transfection of estrogen-dependent cells resulting in their transformation into a tamoxifen-resistant phenotype, proof was provided for the causative role of BCAR genes (Van Agthoven et al, Breast Cancer Res Treat DOI:10.1007/s10549-008-9969-5, 2008). To elucidate the mechanisms how these individual BCAR genes induce cell proliferation in growth-arrested ZR-75-1 cells, we assessed the gene expression patterns between the different groups of cell lines. Keywords: Expression profiling, reference design RNA was isolated from two independent cultures of 69 tamoxifen-resistant cell lines. Detailed information regarding these cell lines with respect to the viral integration sites, was described previously (Van Agthoven et al, Breast Cancer Res Treat DOI:10.1007/s10549-008-9969-5, 2008). Each sample was hybridized in duplicate/triplicate and once in a dye-swap. The mixture of cell lines used as a reference was detailed previously (Jansen et al, J Clin Oncol 23, 732, 2005).
2009-12-09 | E-GEOD-14513 | biostudies-arrayexpress
Project description:Tamoxifen Resistant (TR) gene profile from Breast cancer cell lines T47D and ZR75-1 with their oestrogen-deprieved conterparts were analysed for gene associated with TR. We used Microarray Affymetrix HU133plus 2.0 chips for gene expression of TR cell lines, normalised them against GEO data available for normal T47D (GSM70667) and ZR75-1 (GSM70668). We grew parental breast cancer cell lines in tamoxifen containing media (0.1 microM) for 6 months and labelled them tamoxifen resistant (TR). Oestrogen-Deprieved cells were grown in charcoal-stripped media for 6 months then tamoxifen (0.1 microM) was added to the media and cells maintained a further 6 months and termed Oestrogen deprieved-tamoxifen resistant (ODTR) .
2010-12-31 | E-GEOD-22664 | biostudies-arrayexpress
Project description:Tamoxifen is the most widely used antiestrogen in patients with estrogen receptor (ER) positive breast cancer . However, less than half of patients benefit from tamoxifen treatment and 30-50% acquire resistance and the disease progresses. Resistance to tamoxifen is a serious problem in breast cancer therapy and major efforts are underway to find out underlying mechanisms. To find out the differential expression levels of mRNAs in tamoxifen-sensitive T47D versus tamoxifen-resistant T47D (T47DR) human breast cancer cells, T47DR (tamoxifen-resistant) cell line was established from T47D cells after the following continuous exposure to 1 μmol/L 4-Hydroxytamoxifen (H7904, Sigma, USA) for more than 6 months.Thousands of significantly different mRNA expression levels were found and analysed. Our study provides a reference data for the study of tamoxifen resistance .
2020-06-01 | GSE129544 | GEO
Project description:Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer. However, about 30% of such patients receiving tamoxifen as an adjuvant therapy experience recurrence within 15 years, and most patients with advanced disease eventually develop resistance to tamoxifen. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA-mediated gene regulation in three clinically-relevant tamoxifen-resistant human breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive MCF-7/S0.5 cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all TamRs using both sequencing and LNA-based quantitative PCR technologies.
2015-08-01 | GSE56411 | GEO
Project description:Identification of differently expressed mRNAs in LNPPS overexpression bladder cancer cells
| PRJNA788932 | ENA