Lapatinib and retinoic acid combination treatment of SKBR3 breast cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Fratelli Maddalena
PROVIDER: S-ECPF-MEXP-3192 | biostudies-other |
REPOSITORIES: biostudies-other
Similar Datasets
Project description:SKBR3 cells, which bear both an HER2 and a RARA gene amplification, were treated for 12 or 48 hours with 100 nM retinoic acid, 100 nM lapatinib or the combination.The two drugs synergize and induce massive apoptosis. The aim is to find the molecular mechanism(s) of this synergism. Gene expression profiling was performed using Agilent two-color 4X44K arrays. Original processed data are available in the archive: http://www.ebi.ac.uk/arrayexpress/files/E-MEXP-3192/E-MEXP-3192.additional.zip
2011-10-06 | E-MEXP-3192 | biostudies-arrayexpress
Project description:In SKBR3 cells, simultaneous targeting of RARM-kM-1 with all-trans retinoic acid (ATRA) and HER2 with lapatinib results in synergistic anti-tumor responses. SKBR3 cells were treated with vehicle (DMSO), lapatinib (100 nM), ATRA (100 nM) or lapatinib+ATRA for 36 hours and miRNA expression profile was determined by one-color Agilent microarray experiments.
2015-04-30 | E-MTAB-3097 | biostudies-arrayexpress
Project description:SKBR3-cells, characterized by ERBB2/RARA co-amplification, represent a subgroup of HER2+ breast-cancers sensitive to all-trans retinoic acid (ATRA) and Lapatinib. In this model, the two agents alone or in combination modulate the expression of 174 microRNAs (miRs). These miRs and predicted target-transcripts are organized in four interconnected modules (Module-1 to -4). Module-1 and Module-3 consist of ATRA/Lapatinib up-regulated and potentially anti-oncogenic miRs, while Module-2 contains ATRA/Lapatinib down-regulated and potentially pro-oncogenic miRs. Consistent with this, the expression levels of Module-1/-3 and Module-2 miRs are higher and lower, respectively, in normal mammary tissues relative to ductal-carcinoma-in-situ, invasive-ductal-carcinoma and metastases. This indicates associations between tumor-progression and the expression profiles of Module-1 to -3 miRs. Similar associations are observed with tumor proliferation-scores, staging, size and overall-survival using TCGA (The Cancer Genome Atlas) data. Forced expression of Module-1 miRs, (miR-29a-3p; miR-874-3p) inhibit SKBR3-cell growth and Module-3 miRs (miR-575; miR-1225-5p) reduce growth and motility. Module-2 miRs (miR-125a; miR-193; miR-210) increase SKBR3 cell growth, survival and motility. Some of these effects are of general significance, being replicated in other breast cancer cell lines representing the heterogeneity of this disease. Finally, our study demonstrates that HIPK2-kinase and the PLCXD1-phospholipase-C are novel targets of miR-193a-5p/miR-210-3p and miR-575/miR-1225-5p, respectively.
| S-EPMC4537007 | biostudies-literature
Project description:Breast cancer initiating cells (BCICs), which can fully recapitulate the tumor origin and are often resistant to chemo- and radiotherapy, are currently considered as a major obstacle for breast cancer treatment. Here, we show that BIKDD, a constitutively active mutant form of proapoptotic gene, BIK, effectively induces apoptosis of breast cancer cells and synergizes with lapatinib. Most importantly, BikDD significantly reduces BCICs through co-antagonism of its binding partners Bcl-2, Bcl-xL, and Mcl-1, suggesting a potential therapeutic strategy targeting BCICs. Furthermore, we developed a cancer-specific targeting approach for breast cancer that selectively expresses BikDD in breast cancer cells including BCICs, and demonstrated its potent antitumor activity and synergism with lapatinib in vitro and in vivo.
| S-EPMC3172580 | biostudies-literature
Project description:All-trans retinoic acid (RA), the primary metabolite of vitamin A, controls the development and homeostasis of organisms and tissues. RA and its natural and synthetic derivatives, both known as retinoids, are promising agents in treating and chemopreventing different neoplasias, including breast cancer (BC). Focal adhesion kinase (FAK) is a crucial regulator of cell migration, and its overexpression is associated with tumor metastatic behavior. Thus, pharmaceutical FAK inhibitors (FAKi) have been developed to counter its action. In this work, we hypothesize that the RA plus FAKi (RA + FAKi) approach could improve the inhibition of tumor progression. By in silico analysis and its subsequent validation by qPCR, we confirmed RARA, SRC, and PTK2 (encoding RARα, Src, and FAK, respectively) overexpression in all breast cells tested. We also showed a different pattern of genes up/down-regulated between RA-resistant and RA-sensitive BC cells. In addition, we demonstrated that both RA-resistant BC cells (MDA-MB-231 and MDA-MB-468) display the same behavior after RA treatment, modulating the expression of genes involved in Src-FAK signaling. Furthermore, we demonstrated that although RA and FAKi administered separately decrease viability, adhesion, and migration in mammary adenocarcinoma LM3 cells, their combination exerts a higher effect. Additionally, we show that both drugs individually, as well as in combination, induce the expression of apoptosis markers such as active-caspase-3 and cleaved-PARP1. We also provided evidence that RA effects are extrapolated to other cancer cells, including T-47D BC and the human cervical carcinoma HeLa cells. In an orthotopic assay of LM3 tumor growth, whereas RA and FAKi administered separately reduced tumor growth, the combined treatment induced a more potent inhibition increasing mice survival. Moreover, in an experimental metastatic assay, RA significantly reduced metastatic lung dissemination of LM3 cells. Overall, these results indicate that RA resistance could reflect deregulation of most RA-target genes, including genes encoding components of the Src-FAK pathway. Our study demonstrates that RA plays an essential role in disrupting BC tumor growth and metastatic dissemination in vitro and in vivo by controlling FAK expression and localization. RA plus FAKi exacerbate these effects, thus suggesting that the sensitivity to RA therapies could be increased with FAKi coadministration in BC tumors.
| S-EPMC9564078 | biostudies-literature
Project description:PurposeThis review aims to present the preclinical and clinical data regarding efficacy and safety of lapatinib alone and in combination with other agents in the treatment of human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer.BackgroundHER2-positive (HER2+) breast cancer remains a treatment challenge. It is more aggressive than other breast cancers and it is associated with a poor outcome. Targeted therapy for HER2+ breast cancer has significantly changed the clinical course of the disease. Despite advances in therapy, there remains an unmet need in the treatment of HER2+ breast cancer. Lapatinib is a novel, orally bioavailable epidermal growth factor receptor/HER2+ targeted agent. Many trials have investigated the efficacy and safety of lapatinib alone and in conjunction with other agents in the treatment of HER2+ breast cancer.Methods and resultsPreclinical and clinical trials of lapatinib have shown that it is effective in the treatment on HER2+ breast cancer. More important, studies show that it is effective in the setting of trastuzumab resistance and in the treatment of central nervous system metastases, both of which are current treatment challenges. Furthermore, lapatinib is effective in conjunction with trastuzumab in the treatment of early breast cancer. Data regarding the safety of lapatinib show that it is generally well tolerated; however, multiple studies have shown significant (grade 3 and 4) diarrhea and rash associated with lapatinib, thereby limiting its use. Carditoxicity has not been a significant adverse event associated with the use of lapatinib.ConclusionLapatinib is effective alone and in conjunction with other agents in the treatment of HER2+ breast cancer. However, its use is limited by significant diarrhea and rash.
| S-EPMC3846547 | biostudies-literature
Project description:RNAseq was done using Library protocol =Illumina TruSeq Stranded mRNA Library Preparation Kit with poly(A) selection , HiSeq 101 Cycle Paired-End Sequencing v4
2018-11-30 | GSE114575 | GEO
Project description:To explore the broader impact of kinase inhibitors on breast cancer cells, SKBR3/HER2+ cells were treated with two small molecule drugs, i.e., Lapatinib (10 uM) - a Tyr kinase inhibitor, and Ipatasertib (1 uM) - a Ser/Thr kinase inhibitor. Serum-starved cells (24 h) were exposed for 36 h to Lapatinib/EGF or a combination of Lapatinib/Ipatasertib/EGF. EGF - only stimulated cells were used as control. The EGF concentration was 10 nM throughout all experiments. Proteomic profiles of nuclear and cytoplasmic cell fractions of treated vs non-treated cells were generated by nano-LC-MS/MS using an Orbitrap QE instrument.
2024-08-23 | PXD051094 | Pride
Project description:Ferroptosis is an iron-dependent, oxidative cell death, and is distinct from apoptosis, necrosis and autophagy. In this study, we demonstrated that lysosome disrupting agent, siramesine and a tyrosine kinase inhibitor, lapatinib synergistically induced cell death and reactive oxygen species (ROS) in MDA MB 231, MCF-7, ZR-75 and SKBr3 breast cancer cells over a 24 h time course. Furthermore, the iron chelator deferoxamine (DFO) significantly reduced cytosolic ROS and cell death following treatment with siramesine and lapatinib. Furthermore, we determined that FeCl3 levels were elevated in cells treated with siramesine and lapatinib indicating an iron-dependent cell death, ferroptosis. To confirm this, we treated cells with a potent inhibitor of ferroptosis, ferrastatin-1 that effectively inhibited cell death following siramesine and lapatinib treatment. The increase levels of iron could be due to changes in iron transport. We found that the expression of transferrin, which is responsible for the transport of iron into cells, is increased following treatment with lapatinib alone or in combination with siramesine. Knocking down of transferrin resulted in decreased cell death and ROS after treatment. In addition, ferroportin-1 (FPN) is an iron transport protein, responsible for removal of iron from cells. We found its expression is decreased after treatment with siramesine alone or in combination with lapatinib. Overexpression FPN resulted in decreased ROS and cell death whereas knockdown of FPN increased cell death after siramesine and lapatinib treatment. This indicates a novel induction of ferroptosis through altered iron regulation by treating breast cancer cells with a lysosome disruptor and a tyrosine kinase inhibitor.
| S-EPMC4973350 | biostudies-literature
Project description:Breast cancer is the most common malignancy in women and the appearance of distant metastases produces the death in 98% of cases. The retinoic acid receptor ? (RAR?) is not expressed in 50% of invasive breast carcinoma compared with normal tissue and it has been associated with lymph node metastasis. Our hypothesis is that RAR? protein participates in the metastatic process. T47D and MCF7 breast cancer cell lines were used to perform viability assay, immunobloting, migration assays, RNA interference and immunofluorescence. Administration of retinoic acid (RA) in breast cancer cells induced RAR? gene expression that was greatest after 72 hrs with a concentration 1 ?M. High concentrations of RA increased the expression of RAR? causing an inhibition of the 60% in cell migration and significantly decreased the expression of migration-related proteins [moesin, c-Src and focal adhesion kinase (FAK)]. The treatment with RAR? and RAR? agonists did not affect the cell migration. On the contrary, the addition of the selective retinoid RAR?-agonist (BMS453) significantly reduced cell migration comparable to RA inhibition. When RAR? gene silencing was performed, the RA failed to significantly inhibit migration and resulted ineffective to reduce moesin, c-Src and FAK expressions. RAR? is necessary to inhibit migration induced by RA in breast cancer cells modulating the expression of proteins involved in cell migration.
| S-EPMC4508151 | biostudies-other