scholarly journals Intrinsically Disordered SRC-3/AIB1 Protein Undergoes Homeostatic Nuclear Extrusion by Nuclear Budding While Ectopic Expression Induces Nucleophagy

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1278
Author(s):  
Cabrita ◽  
Renart ◽  
Lau ◽  
Pratt
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Nuclear Membrane ◽  
Breast Cancer Cells ◽  
Protein Quality ◽  
Ectopic Expression ◽  
Breast Cancers ◽  
Creb Binding Protein ◽  
Intrinsically Disordered ◽  
Mcf 7

SRC-3/AIB1 (Amplified in Breast Cancer-1) is a nuclear receptor coactivator for the estrogen receptor in breast cancer cells. It is also an intrinsically disordered protein when not engaged with transcriptional binding partners and degraded upon transcriptional coactivation. Given the amplified expression of SRC-3 in breast cancers, the objective of this study was to determine how increasing SRC-3 protein levels are regulated in MCF-7 breast cancer cells. We found that endogenous SRC-3 was expelled from the nucleus in vesicle-like spheres under normal growth conditions suggesting that this form of nuclear exclusion of SRC-3 is a homeostatic mechanism for regulating nuclear SRC-3 protein. Only SRC-3 not associated with CREB-binding protein (CBP) was extruded from the nucleus. We found that overexpression in MCF-7 cells results in aneuploid senescence and cell death with frequent formation of nuclear aggregates which were consistently juxtaposed to perinuclear microtubules. Transfected SRC-3 was SUMOylated and caused redistribution of nuclear promyelocytic leukemia (PML) bodies and perturbation of the nuclear membrane lamin B1, hallmarks of nucleophagy. Increased SRC-3 protein-induced autophagy and resulted in SUMO-1 localization to the nuclear membrane and formation of protrusions variously containing SRC-3 and chromatin. Aspects of SRC-3 overexpression and toxicity were recapitulated following treatment with clinically relevant agents that stabilize SRC-3 in breast cancer cells. We conclude that amplified SRC-3 levels have major impacts on nuclear protein quality control pathways and may mark cancer cells for sensitivity to protein stabilizing therapeutics.

scholarly journals The Role of Aryl Hydrocarbon Receptor and Crosstalk with Estrogen Receptor in Response of Breast Cancer Cells to the Novel Antitumor Agents Benzothiazoles and Aminoflavone

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Mariana A. Callero ◽  
Andrea I. Loaiza-Pérez
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Aryl Hydrocarbon Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Antitumor Agents ◽  
Breast Cancers ◽  
Nude Mouse Model ◽  
Aryl Hydrocarbon ◽  
Mcf 7

Many estrogen-receptor- (ER-) expressing breast cancers become refractory to ER-based therapies. New antitumor drugs like aminoflavone (AF) and benzothiazoles (Bzs) have been developed and have exquisite antitumor activity in ER+MCF-7 and T47D cells and in a MCF-7 nude mouse model. ER(−) breast cancer cells like MDA-MB-231 are less susceptible. We previously found in MCF-7 cells that these drugs activate the aryl hydrocarbon receptor (AhR) via translocation to the nucleus, induction of AhR-specific DNA binding activity, and expression of CYP1A1, whose transcription is controlled by the AhR-ARNT transcription factor. CYP1A1 metabolizes AF and Bz to a species which directly or after further metabolism damages DNA. In contrast an AhR-deficient variant of MCF-7 or cells with predominantly nuclear AhR expression, such as MDA-MB 231, are resistant. Thus, these drugs, unlike other neoplastic agents, require AhR-mediated signaling to cause DNA damage. This is a new treatment strategy for breast cancers with intact AhR signaling.

scholarly journals lncMat2B regulated by severe hypoxia induces cisplatin resistance by increasing DNA damage repair and tumor-initiating population in breast cancer cells

2020 ◽  
Vol 41 (11) ◽  
pp. 1485-1497 ◽  
Author(s):  
Alfredo García-Venzor ◽  
Edna Ayerim Mandujano-Tinoco ◽  
Araceli Ruiz-Silvestre ◽  
José Manuel Sánchez ◽  
Floria Lizarraga ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Ectopic Expression ◽  
Three Dimensional ◽  
Severe Hypoxia ◽  
Loss Of Function ◽  
Mcf 7

Abstract Multicellular tumor spheroids (MCTSs) constitute a three-dimensional culture system that recapitulates the in vivo tumor microenvironment. Tumor cells cultured as MCTSs present antineoplastic resistance due to the effect of microenvironmental signals acting upon them. In this work, we evaluated the biological function of a new microenvironment-regulated long non-coding RNA, lncMat2B, in breast cancer. In MCTSs, the expression of lncMat2B presented an increase and a zonal heterogeneity, as it was expressed principally in quiescent cells of hypoxic regions of the MCTSs. As expected, functional assays supported the role of severe hypoxia in the regulation of lncMat2B. Moreover, gain- and loss-of-function assays using a transcriptional silencing CRISPR/Cas9 system and gBlock revealed that lncMAT2B regulates the tumor-initiating phenotype. Interestingly, lncMat2B is overexpressed in a cisplatin-resistant MCF-7 cell line, and its ectopic expression in wild type MCF-7 cells increased survival to cisplatin exposure by reducing DNA damage and reactive oxygen species accumulation. lncMAT2B is a possible link between severe hypoxia, tumor-initiating phenotype and drug resistance in breast cancer cells.

scholarly journals Dovitinib Triggers Apoptosis and Autophagic Cell Death by Targeting SHP-1/p-STAT3 Signaling in Human Breast Cancers

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Yi-Han Chiu ◽  
Yi-Yen Lee ◽  
Kuo-Chin Huang ◽  
Cheng-Chi Liu ◽  
Chen-Si Lin
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Ectopic Expression ◽  
Health Concern ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Human Breast ◽  
Stat3 Inhibition

Breast cancer is the most common cancer and the leading cause of cancer deaths in women worldwide. The rising incidence rate and female mortality make it a significant public health concern in recent years. Dovitinib is a novel multitarget receptor tyrosine kinase inhibitor, which has been enrolled in several clinical trials in different cancers. However, its antitumor efficacy has not been well determined in breast cancers. Our results demonstrated that dovitinib showed significant antitumor activity in human breast cancer cell lines with dose- and time-dependent manners. Downregulation of phosphor-(p)-STAT3 and its subsequent effectors Mcl-1 and cyclin D1 was responsible for this drug effect. Ectopic expression of STAT3 rescued the breast cancer cells from cell apoptosis induced by dovitinib. Moreover, SHP-1 inhibitor reversed the downregulation of p-STAT3 induced by dovitinib, indicating that SHP-1 mediated the STAT3 inhibition effect of dovitinib. In addition to apoptosis, we found for the first time that dovitinib also activated autophagy to promote cell death in breast cancer cells. In conclusion, dovitinib induced both apoptosis and autophagy to block the growth of breast cancer cells by regulating the SHP-1-dependent STAT3 inhibition.

Pleiotrophin Secreted from Human Breast Cancer MCF-7-Ptn Cells Activates Stromal Fibroblasts, Induces Epithelial Island Formation, and Remodels the Microenvironment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2568-2568 ◽  
Author(s):  
Masahiko Zuka ◽  
Yunchao Chang ◽  
Zhaoyi Wang ◽  
James R. Berenson ◽  
Thomas F. Deuel
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Breast Cancers ◽  
Human Breast ◽  
Nih3t3 Cells ◽  
Inappropriate Expression ◽  
Nih 3T3 ◽  
Mcf 7

Abstract Pleiotrophin (PTN, Ptn) is an 18 kD cytokine that is expressed in many human breast cancers and its gene is inappropriately expressed in cell lines derived from these breast cancers. To study the siginificance of inappropriate expression of Ptn in human breast cancer cells on surrounding stromal cells, we first compared nude mouse xenografts of MCF-7 and MCF-7-Ptn cells. MCF-7-Ptn cells lack the Receptor Protein Tyrosine Phosphatase (RPTP)b/z, the PTN receptor, and thus are not responsive to PTN through autocrine or paracrine stimulation. The MCF-7-Ptn cell xenografts grew rapidly whereas MCF-7 cells xenografts were barely detectable 6 weeks after injection. MCF-7-Ptn cells that were co-injected with equal numbers of NIH3T3 cells grew even more rapidly in the flanks of the nude mice. Surprisingly, the MCF-7-Ptn cell explants developed a morphological phenotype remarkably similar to that of the human invasive ductal carcinoma. We then co-cultured MCF-7 cells that express Ptn (MCF-7-Ptn cells) with NIH 3T3 cells. Secretion of PTN from MCF-7-Ptn cells induced formation of sharply defined clusters of MCF-7-Ptn cells, termed “epithelial islands”, that were surrounded by dense fibrous bands interspersed with NIH 3T3 cells that morphologically closely resemble carcinoma associated fibroblasts (CAFs). A striking increase in tropoelastin and expression of type IV procollagen mRNA was identified in NIH3T3 cells co-cultured with MCF-7-Ptn cells. Furthermore, different markers often resulting from stromal cell-carcinoma cell interactions in breast cancer, including protein kinase C (PKC)-d, and both human and murine matrix metalloproteinase (MMP) 9 were identified either in cells or in the culture media taken from MCF-7-Ptn/NIH3T3 cell co-cultures. The induction of these biochemical and morphological features in the co-cultures of MCF-7-Ptn and NIH3T3 cells was demonstrated to be Ptn expression dependent, PTN-secretion dependent, and NIH3T3 cell dependent. The data suggest that PTN secretion alone from human breast cancer cells with inappropriate expression of Ptn is sufficient to markedly remodel the microenvironment of the breast cancer cell and induce a morphological transition of the MCF-7-Ptn cells and NIH3T3 cells to patterns resembling breast carcinomas through activation of the PTN/RPTPb/z signaling pathway in NIH3T3 cells and reciprocal signaling between the carcinoma stromal cells and the PTN secreting breast cancer cells.

scholarly journals Chitosan nanoparticle-delivered siRNA reduces CXCR4 expression and sensitizes breast cancer cells to cisplatin

2017 ◽  
Vol 37 (3) ◽  
Author(s):  
Shaonan Yu ◽  
Yan Chen ◽  
Xuefeng Li ◽  
Zhongli Gao ◽  
Guifeng Liu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cxcr4 Expression ◽  
Breast Cancers ◽  
Protein Levels ◽  
Chitosan Nanoparticle ◽  
Increased Sensitivity ◽  
Sirna Group ◽  
Mcf 7

Chemokine (C-X-C motif) receptor 4 (CXCR4) has been reported as a poor prognostic biomarker in human breast cancers, and has been suggested as a promising therapeutic target of breast cancer treatment. The present study aims to investigate the delivery efficiency of siRNA by chitosan into breast cancer cells, and then to examine the regulatory role by chitosan nanoparticle-delivered siRNA on CXCR4 expression and on the chemosensitivity of breast cancer cells. Our results demonstrated that the siRNA could be capsuled by chitosan into nanoparticles with a diameter of 80–110 nm, and with a zeta potential of 20–50 mV. The chitosan nanoparticle delivered siRNA efficiently into breast cancer MCF-7 cells significantly reduced the expression of CXCR4 in both mRNA and protein levels. Moreover, the reduced CXCR4 by chitosan nanoparticle-delivered siRNA was associated with increased sensitivity of breast cancer cells to cisplatin. Reduced growth and increased apoptosis of MCF-7 cells were observed in the CXCR4 siRNA group than in the control siRNA group. Taken together, our results present the treatment potential of chitosan nanoparticle-delivered siRNA targeting CXCR4 in breast cancers.

scholarly journals Effects of BET Inhibitor JQ1 and Interleukin-6 on Breast Cancer Cells

2021 ◽  
Author(s):  
Atefeh Sharif Hoseini ◽  
Masoud Heshmati ◽  
Amin Soltani ◽  
Hedayatollah Shirzad ◽  
Morteza Sedehi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Therapeutic Targets ◽  
Surface Expression ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Bet Inhibitors ◽  
Mcf 7

Abstract Bromodomain and extra-terminal (BET) proteins are recognized acetylated lysine of histone 4 and act as scaffolds to recruit many other proteins to promoters and at enhancers of active genes, especially at the super-enhancers of key genes, driving the transcription process and have been identified as potential therapeutic targets in breast cancer. However, the efficacy of BET inhibitors such as JQ1 in breast cancer therapy is impeded by IL-6 through an as yet defined mechanism. We investigated the interplay between IL-6 and JQ1 in MCF-7 and MDA-MB-231 human breast cancer cells. Here we demonstrate that the efficacy of JQ1 on the inhibition of cell growth and apoptosis was stronger in MDA-MB-231 cells than in MCF-7 cells. Further, MCF-7 cells, but not MDA-MB-231 cells, exhibited increased expression of CXCR4 following IL-6 treatment. JQ1 significantly reduced CXCR4 surface expression in both cell lines and diminished the effects of IL-6 pre-treatment on MCF-7 cells. While IL-6 suppressed the extension of breast cancer stem cells (BCSCs) in MCF-7 cells, JQ1 impeded its inhibitory effect. In addition, in MCF-7 cells JQ1 increased the number of senescent cells in a time-dependent manner. Analysis of gene expression indicated that JQ1 and IL-6 synergistically increase SNAIL expression and decrease c-MYC expression in MCF-7 cells. So, the BET proteins are promising, novel therapeutic targets in late-stage breast cancers.

scholarly journals Narciclasine Targets STAT3 via Distinct Mechanisms in Tamoxifen-Resistant Breast Cancer Cells

2021 ◽  
Author(s):  
Chao Lv ◽  
Yun Huang ◽  
Rui Huang ◽  
Qun Wang ◽  
Hongwei Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Sh2 Domain ◽  
Breast Cancers ◽  
Stat3 Phosphorylation ◽  
Er Positive ◽  
Tamoxifen Resistant ◽  
Mcf 7 ◽  
Positive Breast Cancer

Abstract Background: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in multiple malignant tumors. Compared with regular estrogen receptor (ER)-positive breast cancers, the patients with tamoxifen-resistant breast cancers often exhibit higher level of STAT3 phosphorylation. Narciclasine (Nar) possesses strong inhibiting effects against a variety of cancer cells, however, the underlying antitumor target(s)/mechanism(s) remains barely understood. Methods: Targets prediction of narciclasine was performed by combining connectivity map (CMAP) and drug affinity responsive target stability (DARTS) strategy. Molecular and biochemical methods were used to elucidate the distinct mechanisms of narciclasine targeting STAT3. The narciclasine nano-delivery system was synthesized by thin film hydration method. Xenograft models were established to determine antitumor activity of narciclasine and its liposome in vivo.Results: In this study, we successfully identified the STAT3 was the direct target of Nar through the combination strategies of CMAP and DARTS. In ER-positive breast cancer cells, Nar could suppress phosphorylation, activation, dimerization, and nuclear translocation of STAT3 by directly binding with the STAT3 SH2 domain. Additionally, Nar could also specifically promote total STAT3 degradation via proteasome pathway and reduce the STAT3 protein stability in tamoxifen-resistant breast cancer cells (MCF-7/TR). This distinct mechanism of Nar targeting STAT3 was mainly attributed to the various levels of reactive oxygen species (ROS) in regular and tamoxifen-resistant ER-positive breast cancer cells. Meanwhile, Nar loaded nanoparticles could markedly decrease the protein levels of STAT3 in tumor sites, resulting in significant MCF-7/TR xenograft tumor regression without obvious toxicity. Conclusions: Our findings successfully highlight the STAT3 as the direct therapeutic target of Nar in ER-positive breast cancer cells, especially Nar leaded STAT3 degradation as a promising strategy for the tamoxifen-resistant breast cancer treatment.

scholarly journals Dihydroartemisinin-loaded Magnetic Nanoparticles for Enhanced Chemodynamic Therapy

2019 ◽  
Author(s):  
Shengdi Guo ◽  
Xianxian Yao ◽  
Qin Jiang ◽  
Kuang Wang ◽  
Yuanying Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Magnetic Nanoparticles ◽  
Cancer Cells ◽  
Therapeutic Effect ◽  
Breast Cancer Cells ◽  
Inhibitory Effect ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Ferrous Ions ◽  
Mcf 7

AbstractRecently, chemodynamic therapy (CDT) has represented a new approach for cancer treatment with low toxicity and side effects. Nonetheless, it has been a challenge to improve the therapeutic effect through increasing the amount of reactive oxygen species (ROS). Herein, we increased the amount of ROS agents in the Fenton-like reaction by loading dihydroartemisinin (DHA) which was an artemisinin (ART) derivative containing peroxide groups, into magnetic nanoparticles (MNP), thereby improving the therapeutic effect of CDT. Blank MNP were almost non-cytotoxic, whereas three MNP loading ART-based drugs, MNP-ART, MNP-DHA, and MNP-artesunate (MNP-AS), all showed significant killing effect on breast cancer cells (MCF-7 cells), in which MNP-DHA were the most potent. What’s more, the MNP-DHA showed high toxicity to drug-resistant breast cancer cells (MCF-7/ADR cells), demonstrating its ability to overcome multidrug resistance (MDR). The study revealed that MNP could produce ferrous ions under the acidic condition of tumor microenvironment, which catalyzed DHA to produce large amounts of ROS, leading to cell death. Further experiments also showed that the MNP-DHA had significant inhibitory effect on another two aggressive breast cancer cell lines (MDA-MB-231 and MDA-MB-453 cells), which indicated that the great potential of MNP-DHA for the treatment of intractable breast cancers.

scholarly journals Evidence for Enhanced Exosome Production in Aromatase Inhibitor-Resistant Breast Cancer Cells

2020 ◽  
Vol 21 (16) ◽  
pp. 5841
Author(s):  
Giuseppina Augimeri ◽  
Giusi La Camera ◽  
Luca Gelsomino ◽  
Cinzia Giordano ◽  
Salvatore Panza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Protein Transport ◽  
Small Gtpase ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Breast Cancers ◽  
Mcf 7

Aromatase inhibitors (AIs) represent the standard anti-hormonal therapy for post-menopausal estrogen receptor-positive breast cancer, but their efficacy is limited by the emergence of AI resistance (AIR). Exosomes act as vehicles to engender cancer progression and drug resistance. The goal of this work was to study exosome contribution in AIR mechanisms, using estrogen-dependent MCF-7 breast cancer cells as models and MCF-7 LTED (Long-Term Estrogen Deprived) subline, modeling AIR. We found that exosome secretion was significantly increased in MCF-7 LTED cells compared to MCF-7 cells. MCF-7 LTED cells also exhibited a higher amount of exosomal RNA and proteins than MCF-7 cells. Proteomic analysis revealed significant alterations in the cellular proteome. Indeed, we showed an enrichment of proteins frequently identified in exosomes in MCF-7 LTED cells. The most up-regulated proteins in MCF-7 LTED cells were represented by Rab GTPases, important vesicle transport-regulators in cancer, that are significantly mapped in “small GTPase-mediated signal transduction”, “protein transport” and “vesicle-mediated transport” Gene Ontology categories. Expression of selected Rab GTPases was validated by immunoblotting. Collectively, we evidence, for the first time, that AIR breast cancer cells display an increased capability to release exosomes, which may be associated with an enhanced Rab GTPase expression. These data provide the rationale for further studies directed at clarifying exosome’s role on endocrine therapy, with the aim to offer relevant markers and druggable therapeutic targets for the management of hormone-resistant breast cancers.

scholarly journals Induced Tamoxifen Resistance is Mediated by Increased Methylation of E-Cadherin in Estrogen Receptor-Expressing Breast Cancer Cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Qi Wang ◽  
Melisa Gun ◽  
Xing-yu Hong
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Breast Cancers ◽  
Mesenchymal Transition ◽  
Tamoxifen Resistant ◽  
Mcf 7 ◽  
E Cadherin

Abstract Estrogen receptor-positive breast cancers are treated with tamoxifen, a drug that competitively inhibits the binding of estrogen to its receptor. Resistance to tamoxifen is a major hurdle in effective management of target breast cancer patient population. A number of dynamic changes within the tumor microenvironment, including the phenomenon of epithelial to mesenchymal transition (EMT), determine the response to endocrine therapy. EMT is marked by silencing or suppression of epithelial marker, E-Cadherin and we found significantly down-regulated E-Cadherin, among other epithelial markers, and a significantly up-regulated mesenchymal marker, Twist, among other mesenchymal markers, in a model system that comprised of tamoxifen sensitive MCF-7 cells and their tamoxifen-resistant counterparts, MCF-7-TAM, developed by chronic and escalating exposure of parental cells to tamoxifen. Further, E-cadherin, but not Twist, was differentially expressed in MCF-7-TAM cells because of differential methylation. Treatment with demethylating agent 5-azacytidine increased the expression of E-cadherin thus verifying a role of methylation in its silencing and, moreover, 5-azacytidine treatment also re-sensitized MCF-7-TAM cells to tamoxifen, as evaluated by assays for viability, apoptosis and migration potential. The 5-azacytidine effects were similar to effects of E-cadherin overexpression in MCF-7-TAM cells. This work describes novel mechanism of E-cadherin downregulation in tamoxifen resistant breast cancer cells. Further studies are needed to exploit this information for betterment of breast cancer therapy.

Sign in / Sign up

Export Citation Format

Share Document