Estrogen Receptor Activation Time Course at 3, 6, 12 & 24h in MCF7, T47D and MDA-MB-231 with and without ZMIZ1 knockdown
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE133381 | GEO | 2021/04/27
REPOSITORIES: GEO
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Project description:Estrogen Receptor Activation Time Course at 3, 6, 12 & 24h in MCF7, T47D and MDA-MB-231 with and without ZMIZ1 knockdown
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Project description:Currently the greatest challenge in oncology is the lack of homogeneity of the lesions where different cell components respond differently to treatment. There is growing consensus that monotherapies are insufficient to eradicate the disease and there is an unmet need for more potent combinatorial treatments. We have previously shown that hypericin photodynamic therapy (HYP-PDT) triggers electron transport chain (ETC) inhibition in cell mitochondria. We have also shown that tamoxifen (TAM) enhances cytotoxicity in cells with high respiration, when combined with ETC inhibitors. Herein we introduce a synergistic treatment based on TAM chemotherapy and HYP-PDT. We tested this novel combinatorial treatment (HYPERTAM) in two metabolically different breast cancer cell lines, the triple-negative MDA-MB-231 and the estrogen-receptor-positive MCF7, the former being quite sensitive to HYP-PDT while the latter very responsive to TAM treatment. In addition, we investigated the mode of death, effect of lipid peroxidation, and the effect on cell metabolism. The results were quite astounding. HYPERTAM exhibited over 90% cytotoxicity in both cell lines. This cytotoxicity was in the form of both necrosis and autophagy, while high levels of lipid peroxidation were observed in both cell lines. We, consequently, translated our research to an in vivo pilot study encompassing the MDA-MB-231 and MCF7 tumor models in NOD SCID-γ immunocompromised mice. Both treatment cohorts responded very positively to HYPERTRAM, which significantly prolonged mice survival. HYPERTAM is a potent, synergistic modality, which may lay the foundations for a novel, composite anticancer treatment, effective in diverse tumor types.
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Project description:Human telomeres were one of the first discovered and characterized sequences forming quadruplex structures. Association of these structures with oncogenic and tumor suppressor proteins suggests their important role in cancer development and therapy efficacy. Since cationic porphyrin TMPyP4 is known as G-quadruplex stabilizer and telomerase inhibitor, the aim of the study was to analyze the anticancer properties of this compound in two different human breast-cancer MCF7 and MDA-MB-231 cell lines. The cytotoxicity of TMPyP4 alone or in combination with doxorubicin was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromid) and clonogenic assays, and the cell-cycle alterations were analyzed by flow cytometry. Telomerase expression and activity were evaluated using qPCR and telomeric repeat amplification protocol (TRAP) assays, respectively. The contribution of G-quadruplex inhibitor to protein pathways engaged in cell survival, DNA repair, adhesion, and migration was performed using immunodetection. Scratch assay and functional assessment of migration and cell adhesion were also performed. Consequently, it was revealed that in the short term, TMPyP4 neither revealed cytotoxic effect nor sensitized MCF7 and MDA-MB-231 to doxorubicin, but altered breast-cancer cell adhesion and migration. It suggests that TMPyP4 might substantially contribute to a significant decrease in cancer cell dissemination and, consequently, cancer cell survival reduction. Importantly, this effect might not be associated with telomeres or telomerase.
| S-EPMC6600420 | biostudies-literature
Project description:Polycomb repressive complex PRC1 is essential for gene regulation in numerous cell fate decisions. We show that RING1B (RING2, RNF2) and canonical PRC1 (cPRC1) genes are amplified and overexpressed in breast cancer (BC). Moreover, cPRC1 complexes functionally associate with genes regulated by cell type specific key transcription factors such as estrogen receptor (ER) in ER+ tumor cells and BRD4 in triple negative BC cells. cPRC1 is recruited to active enhancers in a manner independent of PRC2 and RING1B enzymatic activity. RING1B regulates enhancer activity and gene transcription not only by promoting the expression of BC oncogenes but also by regulating chromatin accessibility for oncogenic transcription factors. RING1B recruitment, and thus PRC1 association, to active enhancers occurs in multiple cancers.
2018-10-19 | PXD009570 | Pride
Project description:Golgi phosphoprotein 3 (GOLPH3) has been implicated in the development of carcinomas in many human tissues, and is currently considered a bona fide oncoprotein. Importantly, several tumor types show overexpression of GOLPH3, which is associated with tumor progress and poor prognosis. However, the underlying molecular mechanisms that connect GOLPH3 function with tumorigenicity are poorly understood. Experimental evidence shows that depletion of GOLPH3 abolishes transformation and proliferation of tumor cells in GOLPH3-overexpressing cell lines. Conversely, GOLPH3 overexpression drives transformation of primary cell lines and enhances mouse xenograft tumor growth in vivo. This evidence suggests that overexpression of GOLPH3 could result in distinct features of GOLPH3 in tumor cells compared to that of non-tumorigenic cells. GOLPH3 is a peripheral membrane protein mostly localized at the trans-Golgi network, and its association with Golgi membranes depends on binding to phosphatidylinositol-4-phosphate. GOLPH3 is also contained in a large cytosolic pool that rapidly exchanges with Golgi-associated pools. GOLPH3 has also been observed associated with vesicles and tubules arising from the Golgi, as well as other cellular compartments, and hence it has been implicated in several membrane trafficking events. Whether these and other features are typical to all different types of cells is unknown. Moreover, it remains undetermined how GOLPH3 acts as an oncoprotein at the Golgi. Therefore, to better understand the roles of GOLPH3 in cancer cells, we sought to compare some of its biochemical and cellular properties in the human breast cancer cell lines MCF7 and MDA-MB-231 with that of the non-tumorigenic breast human cell line MCF 10A. We found unexpected differences that support the notion that in different cancer cells, overexpression of GOLPH3 functions in diverse fashions, which may influence specific tumorigenic phenotypes.
| S-EPMC4849736 | biostudies-literature
Project description:This study is to investigate the effect of the PI3K/Akt signaling pathway on the regulation of BRCA1 subcellular localization in triple-negative breast cancer (TNBC) MDA-MB-231 cells and hormone-sensitive T47D cells. We found that heregulin-activated T47D cells showed more nuclear localization of BRCA1, but BRCA1 nuclear localization decreased after the inhibition of the PI3K signaling pathway. In MDA-MB-231 cells, activation or inhibition of the PI3K signaling pathway did not significantly affect cell apoptosis and BRCA1 nuclear translocation (P > 0.05). However, in T47D cells, the activation of the PI3K pathway significantly increased cell apoptosis (P < 0.05). In the heregulin-activated MDA-MB-231 and T47D cells, the phosphorylation of Akt and BRCA1 was significantly increased (P < 0.05), while that was significantly reduced after PI3K pathway inhibition (P < 0.05). The changing trends of the mRNA levels of Akt and BRCA1 in MDA-MB-231 and T47D cells after PI3K pathway activation or inhibition were consistent with the trends of their proteins. In both MDA-MB-231 and T47D cells, BRCA1 phosphorylation is regulated by the PI3K signaling pathway, but the nuclear localization of BRCA1 is different in these two cell lines. Moreover, the apoptosis rates of these two cell lines are different.
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Project description:Since bone metastatic breast cancer is an incurable disease, causing significant morbidity and mortality, understanding of the underlying molecular mechanisms would be highly valuable. Here, we describe in vitro and in vivo evidence for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic and histological observations in the inoculated mice. Genome-wide gene expression profiling of this isogenic cell line pair revealed that all the three genes involved in the L-serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) were upregulated in the highly metastatic variant. This pathway is the primary endogenous source for L-serine in mammalian tissues. Consistently, we observed that the proliferation of MDA-MB-231(SA) cells in serine-free conditions was dependent on PSAT1 expression. In addition, we observed that L-serine is essential for the formation of bone resorbing human osteoclasts and may thus contribute to the vicious cycle of osteolytic bone metastasis. High expression of PHGDH and PSAT1 in primary breast cancer was significantly associated with decreased relapse-free and overall survival of patients and malignant phenotypic features of breast cancer. In conclusion, high expression of serine biosynthesis genes in metastatic breast cancer cells and the stimulating effect of L-serine on osteoclastogenesis and cancer cell proliferation indicate a functionally critical role for serine biosynthesis in bone metastatic breast cancer and thereby an opportunity for targeted therapeutic interventions. Parental MDA-MB-231 cells and MDA-MB-231(SA) cells were cultured in cell culture flasks. RNA was isolated in order to compare the gene expression profiles of these cell variants. Total of two samples. No replicates.
| S-ECPF-GEOD-20085 | biostudies-other
Project description:In the past decades, altered Follistatin‑like 1 (FSTL1) expression has been documented in a variety of cancers, while its functional roles are poorly understood. Particularly in breast cancer, the expression of FSTL1 and its signaling pathway remain to be determined. In the present study, an elevated FSTL1 expression and a supressed cell proliferation were detected in a specific brain metastatic cell line MDA‑MB‑231‑BR (231‑BR), compared with its parental cell line MDA‑MB‑231. However, this protein was hardly detected in the other three breast cancer cell lines. Next, lentiviral vectors encoding FSTL1 or FSTL1 specific shRNAs were used to overexpress or knock down FSTL1 in MDA‑MB‑231 or 231‑BR, respectively (MDA‑MB‑231FSTL1 or 231‑BRsh FSTL1). Results showed that overexpression of FSTL1 inhibited MDA‑MB‑231 cell proliferation, while knockdown of FSTL1 in 231‑BR cells promotes cell proliferation, compared with their corresponding control groups. These results were further confirmed in nude mouse xenografts. The tumor volume in 231‑BR cell-bearing mice was significantly smaller than that of MDA‑MB‑231 group, and reduction of tumor volume was detected in MDA‑MB‑231FSTL1 cell-bearing mice compared with the control group. Previous studies revealed that TGF‑β-Smad2/3 signaling pathway was activated in 231‑BR and MDA‑MB‑231FSTL1 cells, which may contribute to the inhibited cell proliferation. In addition, Smad3 knockdown could restore the inhibition of cell proliferation induced by FSTL1 overexpression in MDA‑MB‑231FSTL1 cells, indicating that the anti‑proliferative effect of FSTL1 overexpression may be associated with Smad3 involved TGF‑β signaling pathway regulation. This study identified FSTL1 as an inhibitor of cell proliferation in MDA‑MB‑231 and 231‑BR cell lines, which may provide new insights into the development and management of breast cancer.
| S-EPMC5780039 | biostudies-literature
Project description:Breast cancer remains a leading cause of death in women worldwide. Although breast cancer therapies have greatly advanced in recent years, many patients still develop tumour recurrence and metastasis, and eventually succumb to the disease due to chemoresistance. Citral has been reported to show cytotoxic effect on various cancer cell lines. However, the potential of citral to specifically target the drug resistant breast cancer cells has not yet been tested, which was the focus of our current study.The cytotoxic activity of citral was first tested on MDA-MB-231 cells in vitro by MTT assay. Subsequently, spheroids of MDA-MB-231 breast cancer cells were developed and treated with citral at different concentrations. Doxorubicin, cisplatin and tamoxifen were used as positive controls to evaluate the drug resistance phenotype of MDA-MB-231 spheroids. In addition, apoptosis study was performed using AnnexinV/7AAD flowcytometry. Aldefluor assay was also carried out to examine whether citral could inhibit the ALDH-positive population, while the potential mechanism of the effect of citral was carried out by using quantitative real time- PCR followed by western blotting analysis.Citral was able to inhibit the growth of the MDA-MB-231 spheroids when compared to a monolayer culture of MDA-MB-231 cells at a lower IC50 value. To confirm the inhibition of spheroid self-renewal capacity, the primary spheroids were then cultured to additional passages in the absence of citral. A significant reduction in the number of secondary spheroids were formed, suggesting the reduction of self-renewal capacity of these aldehyde dehydrogenase positive (ALDH+) drug resistant spheroids. Moreover, the AnnexinV/7AAD results demonstrated that citral induced both early and late apoptotic changes in a dose-dependent manner compared to the vehicle control. Furthermore, citral treated spheroids showed lower cell renewal capacity compared to the vehicle control spheroids in the mammosphere formation assay. Gene expression studies using quantitative real time PCR and Western blotting assays showed that citral was able to suppress the self-renewal capacity of spheroids and downregulate the Wnt/?-catenin pathway.The results suggest that citral could be a potential new agent which can eliminate drug-resistant breast cancer cells in a spheroid model via inducing apoptosis.
| S-EPMC5809808 | biostudies-literature
Project description:MiR-544 was inhibited by either a miR-544 antagomir or compound 1 under hypoxic conditions in MDA-MB-231 cells MiRNA microarray was utilized to examine the specificity of 1 for miR-544. 3 MDA-MB-231 samples treated with a miR-544 antagomir or compound 1 were subjected to hypoxia for a period of 5 days. After 5 days, samples were pooled and subjected to miRNA microarray analysis.
| S-ECPF-GEOD-64436 | biostudies-other