Tamoxifen treatment of MCF-7 breastcancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Holdhus Rita
PROVIDER: S-ECPF-MTAB-2729 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Estrogen receptors are indicators of breast cancer adaptability to endocrine therapies, such as tamoxifen. Deficiency or absence of estrogen receptor α (ER-α) in breast cancer cells results in reduced efficacy of endocrine therapy. Here, we investigated the effect of combined tamoxifen and pentadecanoic acid therapy on ER-α-under-expressing breast cancer cells. Drug resistance gene expression patterns were determined by RNA sequencing analysis and in vitro experiments. For the first time, we demonstrate that the combined treatment of pentadecanoic acid, an odd-chain fatty acid, and tamoxifen synergistically suppresses the growth of human breast carcinoma MCF-7 stem cells (MCF-7/SCs), which were found to be tamoxifen-resistant and showed reduced ER-α expression compared with the parental MCF-7 cells. In addition, the combined treatment synergistically induced apoptosis and accumulation of sub-G1 cells and suppressed epithelial-to-mesenchymal transition (EMT). Exposure to this combination induces re-expression of ER-α at the transcriptional and protein levels, along with suppression of critical survival signal pathways, such as ERK1/2, MAPK, EGFR, and mTOR. Collectively, decreased ER-α expression was restored by pentadecanoic acid treatment, resulting in reversal of tamoxifen resistance. Overall, pentadecanoic acid exhibits the potential to enhance the efficacy of endocrine therapy in the treatment of ER-α-under-expressing breast cancer cells.
| S-EPMC9570034 | biostudies-literature
Project description:The consumption of coffee has been suggested to effectively enhance the therapeutic effects of tamoxifen against breast cancer; however, the underlying molecular mechanisms remain unclear. We herein attempted to clarify how coffee decoction exerts anti-cancer effects in cooperation with tamoxifen using the estrogen receptor α (ERα)-positive breast cancer cell line, MCF-7. The results obtained showed that coffee decoction down-regulated the expression of ERα, which was attributed to caffeine inhibiting its transcription. Coffee decoction cooperated with tamoxifen to induce cell-cycle arrest and apoptotic cell death, which may have been mediated by decreases in cyclin D1 expression and the activation of p53 tumor suppressor. The inclusion of caffeine in coffee decoction was essential, but not sufficient, to induce cell-cycle arrest and apoptotic cell death, suggesting the requirement of unknown compound(s) in coffee decoction to decrease cyclin D1 expression and activate apoptotic signaling cascades including p53. The activation of p53 through the cooperative effects of these unidentified component(s), caffeine, and tamoxifen appeared to be due to the suppression of the ERK and Akt pathways. Although the mechanisms by which the suppression of these pathways induces p53-mediated apoptotic cell death remain unclear, the combination of decaffeinated coffee, caffeine, and tamoxifen also caused cell-cycle arrest and apoptotic cell death, suggesting that unknown compound(s) present in decaffeinated coffee cooperate with caffeine and tamoxifen.
| S-EPMC7659352 | biostudies-literature
Project description:Tamoxifen is an anti-estrogen drug used in the treatment of Estrogen Receptor (ER) positive breast cancer. Effects and side effects of tamoxifen is the sum of tamoxifen and all its metabolites. Using concentrations that mimic the clinical situation we examined effects of 4OHtam, 4OHNDtam and NDtam on global gene expression in 17beta-estradiol (E2) treated MCF-7 cells.
2014-10-24 | E-MTAB-2729 | biostudies-arrayexpress
Project description:Microarrays identified miRNAs differentially expressed and 4-hydroxytamoxifen (4-OHT) regulated in MCF-7 endocrine-sensitive versus resistant LY2 human breast cancer cells. 97 miRNAs were differentially expressed in MCF-7 versus LY2 cells. Opposite expression of miRs-10a, 21, 22, 29a, 93, 125b, 181, 200a, 200b, 200c, 205, and 222 was confirmed. Bioinformatic analyses to impute the biological significance of these miRNAs identified 36 predicted gene targets from those regulated by 4-OHT in MCF-7 cells. Agreement in the direction of anticipated regulation was detected for 12 putative targets. These miRNAs with opposite expression between the two cell lines may be involved in endocrine resistance.
| S-EPMC3214732 | biostudies-literature
Project description:PurposeTamoxifen (TAM) is a non-steroidal antiestrogen drug, used in the prevention and treatment of all stages of hormone-responsive breast cancer. Simvastatin (SIM) is a lipid-lowering agent and has been shown to inhibit cancer cell growth. The study aimed to investigate the effect of the combination of TAM and SIM in the treatment of estrogen receptor positive (ER+) breast cancer cell line, MCF-7, and in mice-bearing Ehrlich solid tumors.MethodsMCF-7 cells were treated with different concentrations of TAM or/and SIM for 72 hours and the effects of the combination treatment on cytotoxicity, oxidative stress markers, apoptosis, angiogenesis, and metastasis were investigated using different techniques. In addition, tumor volume, oxidative markers, and inflammatory markers of the combined therapy were explored in mice bearing solid EAC tumors.ResultsThe results showed that treatment of MCF-7 cells with the combination of 10 µM TAM, and 2 µM SIM significantly inhibited the increase in oxidative stress markers, LDH, and NF-kB induced by TAM. In addition, there was a significant decrease in the total apoptotic ratio, caspase-3 activity, and glucose uptake, while there was a non-significant change in Bax/bcl-2 ratio compared to the TAM-treated group. Using the isobologram equation, the drug interaction was antagonistic with combination index, CI=1.18. On the other hand, the combination regimen decreased VEGF, and matrix metalloproteinases, MMP 2&9 compared to TAM-treated cells. Additionally, in vivo, the combination regimen resulted in a non-significant decrease in the tumor volume, decreased oxidative markers, and the protein expression of TNF-α, and NF-κB compared to the TAM treated group.ConclusionAlthough the combination regimen of TAM and SIM showed an antagonistic drug interaction in MCF-7 breast cancer, it displayed favorable antiangiogenic, anti-metastatic, and anti-inflammatory effects.
| S-EPMC6886548 | biostudies-literature
Project description:Tamoxifen is the standard adjuvant endocrine therapy for estrogen-receptor positive premenopausal breast cancer patients. However, tamoxifen resistance is frequently observed under therapy. A tamoxifen resistant cell line has been generated from the estrogen receptor positive mamma carcinoma cell line MCF-7 and was analyzed for putative differences in the aldehyde defence system and accumulation of advanced glycation end products (AGE). In comparison to wt MCF-7 cells, these tamoxifen resistant cells were more sensitive to the dicarbonyl compounds glyoxal and methylglyoxal and displayed increased caspase activity, p38-MAPK- and IκBα-phosphorylation. However, mRNA accumulation of the aldehyde- and AGE-defence enzymes glyoxalase-1 and -2 (GLO1, GLO2) as well as fructosamine-3-kinase (FN3K) was not significantly altered. Tamoxifen resistant cells contained less free sulfhydryl-groups (glutathione) suggesting that the increased sensitivity towards the dicarbonyls was due to a higher sensitivity towards reactive oxygen species which are associated with dicarbonyl stress. To further analyse, if these data are of more general importance, key experiments were replicated with tamoxifen resistant MCF-7 cell lines from two independent sources. These cell lines were also more sensitive to aldehydes, especially glyoxal, but were different in their cellular signalling responses to the aldehydes. In conclusion, glyoxalases and other aldehyde defence enzymes might represent a promising target for the therapy of tamoxifen resistant breast cancers.
| S-EPMC4077828 | biostudies-literature
Project description:The clinical studies for breast cancer (BC) are now assessing the efficacy of 2-Methoxyestradiol (2-ME), a naturally occurring derivative of estradiol. Our study aimed to explore the potential of combining the 2-ME and tamoxifen (TAM) on sensitization of TAM-resistant cells using LCC2 the TAM-resistant cells as a model and comparing the results to the sensitive cells MCF-7. Sulphorhodamine-B (SRB) assay is used to examine the 2-ME chemo-sensitizing impact on the cytotoxicity of TAM on LCC2 cells. Colorimetric assay kits were used to assess the level of the apoptosis-related markers caspases 3, Bcl2, and Bax in cell lysate. Hypoxia-inducible factor 1 alpha (HIF-1α) expression was measured using western blotting. Total cholesterol and triglyceride (TG) levels were examined colorimetrically, using the BIOLABO kit. The use of 2-ME enhanced the cytotoxic effects of TAM and effectively reversed TAM resistance. This was achieved by inhibiting the expression of HIF-1α, while concurrently increasing the levels of apoptotic marker caspase-3, as well as the pro-apoptotic protein Bax. Additionally, there was a reduction in the levels of Bcl2, an anti-apoptotic protein. Furthermore, a reduction in TG and cholesterol levels was noted. Our findings show that HIF-1α plays an important role in TAM resistance and that suppression of HIF-1α by 2-ME-mediated sensitization of BC-resistant cells to TAM. Therefore, the concurrent administration of TAM/2-ME might potentially serve as a viable therapeutic approach to address TAM resistance and enhance the overall therapy efficacy for patients with BC.
| S-EPMC11339102 | biostudies-literature
Project description:Tamoxifen is widely used as a highly effective drug for treating estrogen‑receptor (ER) alpha‑positive breast cancer. However, tamoxifen resistance developed during cancer treatment remains a significant challenge. Tongue cancer resistance‑related protein1 (TCRP1), which is recognized as a novel drug target, is related to chemo‑resistance in human cancers, moreover, it is often overexpressed in various cancer cells, such as in lung cancer, breast cancer, and tongue cancer. However, the effects of TCRP1 on tamoxifen‑resistant breast cancer cells and tissues are far from clear. The present study revealed that TCRP1 induced tamoxifen resistance in breast cancer cells. Western blotting, quantitative real‑time polymerase chain reaction (RT‑PCR) and immunohistochemical staining were performed to detect the expression level of TCRP1 in vivo and in vitro between primary breast cancer tissues and tamoxifen‑resistant breast cancer tissues. The data revealed that the expression of TCRP1 was upregulated in the tamoxifen‑resistant breast cancer tissues and human breast cancer cell line, MCF‑7. Further study revealed that knocking down TCRP1 inhibited the growth of MCF‑7 cells with tamoxifen‑resistance (MCF7‑R cells) and induced cell apoptosis. Moreover, TCRP1 promoted serum‑ and glucocorticoid‑inducible kinase 1 (SGK1) activation via phosphorylation of phosphoinositide‑dependent kinase 1 (PDK1) in MCF7‑R cells. In addition, it was also observed that knocking down TCRP1 inhibited tumorigenesis of MCF‑7 cells in nude mice. In conclusion, these data indicated that TCRP1 could induce tamoxifen resistance by regulating the PDK1/SGK1 signaling pathway. Thus, TCRP1 could be explored as a promising candidate for treating tamoxifen‑resistant breast cancer in the future.
| S-EPMC7160545 | biostudies-literature
Project description:The proteins in an MCF-7 cell line were probed for tamoxifen (TAM) and n-desmethyl tamoxifen (NDT) induced stability changes using the Stability of Proteins from Rates of Oxidation (SPROX) technique in combination with two different quantitative proteomics strategies, including one based on SILAC and one based on isobaric mass tags. Over 1000 proteins were assayed for TAM- and NDT-induced protein stability changes, and a total of 163 and 200 protein hits were identified in the TAM and NDT studies, respectively. A subset of 27 high-confidence protein hits were reproducibly identified with both proteomics strategies and/or with multiple peptide probes. One-third of the high-confidence hits have previously established experimental links to the estrogen receptor, and nearly all of the high-confidence hits have established links to breast cancer. One high-confidence protein hit that has known estrogen receptor binding properties, Y-box binding protein 1 (YBX1), was further validated as a direct binding target of TAM using both the SPROX and pulse proteolysis techniques. Proteins with TAM- and/or NDT-induced expression level changes were also identified in the SILAC-SPROX experiments. These proteins with expression level changes included only a small fraction of those with TAM- and/or NDT-induced stability changes.
| S-EPMC5695045 | biostudies-literature
Project description:While selective estrogen receptor modulators, such as tamoxifen, have contributed to increased survival in patients with hormone receptor-positive breast cancer, the development of resistance to these therapies has led to the need to investigate other targetable pathways involved in oncogenic signaling. Approval of the mTOR inhibitor everolimus in the therapy of secondary endocrine resistance demonstrates the validity of this approach. Importantly, mTOR activation regulates eukaryotic messenger RNA translation. Eukaryotic translation initiation factor 4E (eIF4E), a component of the cap-dependent translation complex eIF4F, confers resistance to drug-induced apoptosis when overexpressed in multiple cell types. The eIF4F complex is downstream of multiple oncogenic pathways, including mTOR, making it an appealing drug target. Here, we show that the eIF4F translation pathway was hyperactive in tamoxifen-resistant (TamR) MCF-7L breast cancer cells. While overexpression of eIF4E was not sufficient to confer resistance to tamoxifen in MCF-7L cells, its function was necessary to maintain resistance in TamR cells. Targeting the eIF4E subunit of the eIF4F complex through its degradation using an antisense oligonucleotide (ASO) or via sequestration using a mutant 4E-BP1 inhibited the proliferation and colony formation of TamR cells and partially restored sensitivity to tamoxifen. Further, the use of these agents also resulted in cell cycle arrest and induction of apoptosis in TamR cells. Finally, the use of a pharmacologic agent which inhibited the eIF4E-eIF4G interaction also decreased the proliferation and anchorage-dependent colony formation in TamR cells. These results highlight the eIF4F complex as a promising target for patients with acquired resistance to tamoxifen and, potentially, other endocrine therapies.
| S-EPMC5518927 | biostudies-literature