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Gene expression profiles of Herceptin-resistant breast cancer cells

ABSTRACT: Herceptin (trastuzumab) is a humanized monoclonal antibody targeted to the Her2 receptor tyrosine kinase. Despite a robust response rate to Herceptin-based therapies in Her2-positive patients, resistance frequently arises within one year of the initial response. To address the mechanism of Herceptin resistance, we selected clonal variants of Her2-positive BT474 human breast cancer cells (BT/HerR) that are highly resistant to the anti-proliferative effects of Herceptin in the presence of 0.2 uM or 1.0 uM Herceptin. Our original report on these cell lines demonstrated sustained PI3K/Akt signaling and sensitivity to PI3K inhibitors in BT/HerR cells in the presence of Herceptin, suggesting dysregulation of that pathway as an essential component of Herceptin-resistant proliferation. To address the mechanism by which BT/HerR cells and their PI3K/Akt signaling pathway became resistant to Herceptin, we analyzed gene expression profiles of two clones (BT/HerR1.0C and BT/HerR 1.0E) that were selected in 1.0 uM Herceptin and two clones (BT/HerR0.2D and BT/HerR 0.2J) that were selected in 0.2 uM Herceptin, in comparison to the Herceptin sensitive BT474 parent cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE15043 | GEO | 2009/08/21

SECONDARY ACCESSION(S): PRJNA114809

REPOSITORIES: GEO

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Gene expression profiles of Herceptin-resistant breast cancer cells

Project description:Herceptin (trastuzumab) is a humanized monoclonal antibody targeted to the Her2 receptor tyrosine kinase. Despite a robust response rate to Herceptin-based therapies in Her2-positive patients, resistance frequently arises within one year of the initial response. To address the mechanism of Herceptin resistance, we selected clonal variants of Her2-positive BT474 human breast cancer cells (BT/HerR) that are highly resistant to the anti-proliferative effects of Herceptin in the presence of 0.2 uM or 1.0 uM Herceptin. Our original report on these cell lines demonstrated sustained PI3K/Akt signaling and sensitivity to PI3K inhibitors in BT/HerR cells in the presence of Herceptin, suggesting dysregulation of that pathway as an essential component of Herceptin-resistant proliferation. To address the mechanism by which BT/HerR cells and their PI3K/Akt signaling pathway became resistant to Herceptin, we analyzed gene expression profiles of two clones (BT/HerR1.0C and BT/HerR 1.0E) that were selected in 1.0 uM Herceptin and two clones (BT/HerR0.2D and BT/HerR 0.2J) that were selected in 0.2 uM Herceptin, in comparison to the Herceptin sensitive BT474 parent cells. Total cellular RNAs were extracted from BT474 (control) and four BT/HerR subclones, two that were originally selected in 1.0 uM Herceptin and two that were originally selected in 0.2 uM Herceptin. Two RNA samples independently prepared from each clone were analyzed.

2009-08-21 | E-GEOD-15043 | biostudies-arrayexpress

BT474 and BT474-J4 microarray data

Project description:These data provide scientific information to understand the mechanism of action of lapatinib resistance in HER2-positive patients and to test the combination of HER2-targeted agents and GSK1363089 (foretinib) in the clinic by using an acquired lapatinib-resistant cell line. Cell lines (BT474, an HER2-positive and lapatinib-sensitive cell line; BT474-J4, an acquired lapatinib-resistant cell line) were treated with lapatinib alone (1uM), foretinib (GSK1363089) alone (0.1 uM), a combination of lapatinib (1 uM) and foretinib (0.1 uM), or DMSO control for 24 hours. Triplicates were performed.

2011-09-19 | E-GEOD-16179 | biostudies-arrayexpress

Treatment effects of trastuzumab and TDM-1 in a murine model of breast cancer brain metastasis

Project description:Background: Central nervous system (CNS) metastases represent a major problem in the treatment of HER2-positive breast cancer due to the disappointing efficacy of HER2-targeted therapies in the brain microenvironment. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in preclinical models of brain metastases. Methods: We treated mice bearing BT474 or MDA-MB-361 tumors in the CNS (N=9-11 per group), or cancer cells grown in organotypic brain slice cultures with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling. All statistical tests were two-sided. Results: T-DM1 significantly delayed the growth of HER2-positive breast cancer brain metastases compared to trastuzumab. These findings were consistent between HER2-driven and PI3K-driven tumors. The activity of T-DM1 resulted in a striking survival benefit (median survival for BT474 tumors: 28d for trastuzumab vs 112d for T-DM1, HR=6.2, 95% CI=6.1 to 85.84; P<.001). No difference in drug distribution and HER2-signaling was revealed between the two groups. However, T-DM1 led to a significant increase in tumor cell apoptosis (One-way ANOVA for ApopTag, p<.001), which was associated with mitotic catastrophe. Conclusions: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven and PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. Clinical investigation of T-DM1 for patients with CNS metastases from HER2-positive breast cancer is warranted. Comparison of trastuzumab (n=4) and TDM-1 (n=4) treated BT-474 human breast carcinoma cells growing in murine brain

2015-11-09 | E-GEOD-69042 | biostudies-arrayexpress

mRNA profiling reveals determinants of trastuzumab efficiency in HER2-positive breast cancer

Project description:The intention was to detect genes that are determining trastuzumab efficiency in HER2-positive breast cancer cell lines with different resistance phenotypes. While BT474 should be sensitive to the drug treatment, HCC1954 is expected to be resistant due to a PI3K mutation. The cell line BTR50 has been derived from BT474 and was cultured to be resistant as well. Based on RNA-Seq data, we performed differential expression analyses on these breast cancer cell lines with and without trastuzumab treatment. In detail, five separate tests were performed, namely resistant cells vs. wild type, i.e. HCC1954 and BTR50 vs. BT474, respectively, and untreated vs. drug treated cells. The significant genes of the first two tests should contribute to resistance. The significant genes of the test BT474 vs. its drug treated version should contribute to the trastuzumab effect. To exclude false positives from the combined gene set (#64), we removed ten genes that were also significant in the test BTR50 vs. its drug treated version. This way we ended up with 54 genes that are very likely to determine trastuzumab efficiency in HER2-positive breast cancer cell lines. mRNA profiles of human breast cancer cell lines were generated by deep sequencing using Illumina HiSeq 2000. The cell lines BT474 and HCC1954 were analyzed with and without trastuzumab treatment. HCC1954 is known to be trastuzumab resistant. Additionally, the cell line BTR50 was generated as resistant version of BT474, and was analyzed with and without trastuzumab as well.

2015-04-21 | E-GEOD-55005 | biostudies-arrayexpress

mRNA profiling reveals determinants of trastuzumab efficiency in HER2-positive breast cancer

2015-04-21 | GSE55005 | GEO

Feng et al 2019 - Microarray Raw Data

Project description:In order to identify mechanisms of drug resistance to HER2-targeted therapy, we performed cDNA microarray analysis on drug naiive BT474 and drug resistant BT474 cells treated with lapatinib for 0, 10, and 20 hrs.

2020-04-14 | GSE136304 | GEO

Human breast cancer cells: parental v.s lapatinib-resistant clone

Project description:Transcriptional profiling of human HER2-positive BT474 breast cancer cells comparing control untreated cancer cells with lapatinib-resistant clone established by chronic treatment with lapatinib

2013-10-31 | GSE51889 | GEO

Human breast cancer cells: parental v.s lapatinib-resistant clone

2013-10-31 | E-GEOD-51889 | biostudies-arrayexpress

Treatment effects of trastuzumab and TDM-1 in a murine model of breast cancer brain metastasis

2015-11-09 | GSE69042 | GEO

RNA-sequencing of tamoxifen-resistant and -sensitive breast cancer cell lines.

Project description:We performed RNA-sequencing on 7 tamoxifen-resistant (MCF-7 Tam1, T-47D Tam1, T-47D Tam2, ZR-75-1 Tam1, ZR-75-1 Tam2, BT474 Tam1 and BT-474 Tam2) and their isogenic parental (MCF-7, T-47D, ZR-75-1 and BT-474) breast cancer cell lines. The tamoxifen-resistant cell lines were generated from the parentel cell lines by continuous administration of 1 µM 4-OH-tamoxifen for eight to twelve months. RNA- sequencing was performed to determine the changes in the expression of genes in the resistant clones as well as pathways. In addition, we compared the expression changes of the cell lines with those of the GSE58708 data set which we reanalyzied in our pipeline.

2018-08-30 | GSE111151 | GEO

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