Expression data from MCF7 tumor xenografts treated with either single agent BMS754807, or Tamoxifen or Letrozole alone; or Tamoxifen or Letrozole in combination with BMS754807 for 28 days
Ontology highlight
ABSTRACT: breast cancer. Combined IGF and estrogen-targeted therapy may improve the benefit of hormonal therapy alone. We employed a postmenopausal model of estrogen-dependent breast cancer in vitro and in vivo using the aromatase-expressing MCF-7/AC-1cells. Using this model, we investigated the anti-tumor effects of the dual IGF-1R/InsR tyrosine kinase inhibitor, BMS-754807 alone and in combination with letrozole or tamoxifen in vivo. We used microarrays to compare gene expression changes of MCF7 breast xenograft treated with either BMS754807, or Tamoxifen or Letrozole alone; or Tamoxifen or Letrozole in combination with BMS754807 for 28 days Breast xenograft MCF7 bearing mice treated with either BMS754807, or Tamoxifen or Letrozole alone; or Tamoxifen or Letrozole in combination with BMS754807 for 28 days. RNA were extracted from tumors and hybridizedon Affymetrix microarrays to compare gene expression changes
Project description:breast cancer. Combined IGF and estrogen-targeted therapy may improve the benefit of hormonal therapy alone. We employed a postmenopausal model of estrogen-dependent breast cancer in vitro and in vivo using the aromatase-expressing MCF-7/AC-1cells. Using this model, we investigated the anti-tumor effects of the dual IGF-1R/InsR tyrosine kinase inhibitor, BMS-754807 alone and in combination with letrozole or tamoxifen in vivo. We used microarrays to compare gene expression changes of MCF7 breast xenograft treated with either BMS754807, or Tamoxifen or Letrozole alone; or Tamoxifen or Letrozole in combination with BMS754807 for 28 days
Project description:Anti-estrogens and aromatase inhibitors are important drugs in the treatment of estrogen-dependent breast cancer. In order to investigate the effects of these drugs on gene expression in breast cancer cells, we treated estrogen receptor-positive MCF-7 cells, stably transfected with the aromatase gene (known as MCF-7aro cells), with testosterone, 17β-estradiol, two aromatase inhibitors (letrozole and anastrozole), and an anti-estrogen (tamoxifen). Microarray analyses using Affymetrix Human Genome U133A GeneChips were carried out using total RNA isolated from the control and treated cells. When comparing the effect of each inhibitor on gene expression we observe that letrozole and anastrozole are more similar in terms of the genes they affect, compared to treatment with tamoxifen. The results of this study provide us with a better understanding of the actions of both aromatase inhibitors and anti-estrogens at the molecular level. We believe that the results of this study serve as the first step in identifying unique expression patterns following drug treatment, and that this will ultimately be useful in customizing patient treatment strategies for estrogen-dependent breast cancer. The data presented here have been processed using the R-Project Bioconductor statistical tools package using the affy library. The following were applied: RMA background correction, pmonly probe-level correction, quantile normalization, avgdiff summary method. Raw data is provided in the form of .CEL files. Keywords = estrogen-dependent breast cancer Keywords = aromatase Keywords: other
Project description:We generated carcinoma-associated fibroblast (CAF) primary cultures from 6 patients with estrogen receptor positive invasive ductal breast carcinoma, co-cultured them with MCF7 cells in estrogen-deprived culture medium and compared their gene expression profiles before and after letrozole treatment. We observed distinct changes in the gene expression profile of CAFs co-cultured with MCF7 cells after letrozole treatment.
Project description:The overarching goal of this study was to explore the antitumor activity of Z-endoxifen, a tamoxifen metabolite, with first-line endocrine therapies tamoxifen and letrozole in the letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1), and with second-line endocrine therapies including tamoxifen, fulvestrant, exemestane, and exemestane plus everolimus, in letrozole-resistant MCF7 model (MCF7LR) in vivo. We used microarray to identify genes that are commonly and differently reguated by Z-endoxifen and tamoxifen treatments in the letrozole-resistant MCF7LR tumors.
Project description:To investigate response or resistance to endocrine therapy, mice with targeted over-expression of Esr1 or CYP19A1 to mammary epithelial cells were employed, representing two direct pathophysiological interventions in estrogen pathway signaling. Both Esr1 and CYP19A1 over-expressing mice responded to letrozole with reduced HAN prevalence and decreased mammary epithelial cell proliferation. CYP19A1 over-expressing mice were tamoxifen-sensitive but Esr1 over-expressing mice were tamoxifen-resistant. Increased ER expression occurred with tamoxifen resistance but no consistent changes in progesterone receptor, pSTAT3, pSTAT5, cyclin D1 or cyclin E levels in association with response or resistance was found. RNA-seq was employed to seek a transcriptome predictive of tamoxifen resistance using these models and a second tamoxifen-resistant model, BRCA1 deficient/Trp53 haploinsufficient mice. Sixty-eight genes associated with immune system processing were upregulated in tamoxifen-resistant Esr1 and Brca1 deficient mice whereas genes related to aromatic compound metabolic process were upregulated in tamoxifen-sensitive CYP19A1 mice. Interferon Regulatory Factor 7 was identified as a key transcription factor regulating these 68 immune processing genes. Two loci encoding novel transcripts with high homology to human IGLL1 were uniquely upregulated in the tamoxifen-resistant models. Letrozole proved to be a successful alternative to tamoxifen. Further study of transcriptional changes associated with tamoxifen resistance including immune-related genes could expand our mechanistic understanding and lead to biomarkers predictive of escape or response to endocrine therapies.
Project description:We report mRNA profiles of human breast cancer cell lines, MCF7 parental, and MCF7-derived tamoxifen resistant cell lines MCF7-TR1 and MCF7-TR2.
Project description:Tamoxifen is the most widely administered adjuvant first-line hormone therapy for Estrogen receptor α (ERα) positive breast cancer patients. However, one from three patients will develop resistance, while the underlying molecular mechanisms are currently unclear. Recent studies reported that abnormal expression of miRNAs played a role in cancer progress. To study the potential function of miRNAs in tamoxifen resistance, Affymetrix GeneChip® miRNA 3.0 microarray was employed to identify differentially expressed miRNAs between tamoxifen sensitive MCF7 parent (MCF7-Pa) cells and induced resistant (MCF7-Re) cells.
Project description:To investigate response or resistance to endocrine therapy, mice with targeted over-expression of Esr1 or CYP19A1 to mammary epithelial cells were employed, representing two direct pathophysiological interventions in estrogen pathway signaling. Both Esr1 and CYP19A1 over-expressing mice responded to letrozole with reduced HAN prevalence and decreased mammary epithelial cell proliferation. CYP19A1 over-expressing mice were tamoxifen-sensitive but Esr1 over-expressing mice were tamoxifen-resistant. Increased ER expression occurred with tamoxifen resistance but no consistent changes in progesterone receptor, pSTAT3, pSTAT5, cyclin D1 or cyclin E levels in association with response or resistance was found. RNA-seq was employed to seek a transcriptome predictive of tamoxifen resistance using these models and a second tamoxifen-resistant model, BRCA1 deficient/Trp53 haploinsufficient mice. Sixty-eight genes associated with immune system processing were upregulated in tamoxifen-resistant Esr1 and Brca1 deficient mice whereas genes related to aromatic compound metabolic process were upregulated in tamoxifen-sensitive CYP19A1 mice. Interferon Regulatory Factor 7 was identified as a key transcription factor regulating these 68 immune processing genes. Two loci encoding novel transcripts with high homology to human IGLL1 were uniquely upregulated in the tamoxifen-resistant models. Letrozole proved to be a successful alternative to tamoxifen. Further study of transcriptional changes associated with tamoxifen resistance including immune-related genes could expand our mechanistic understanding and lead to biomarkers predictive of escape or response to endocrine therapies. Single- and paired-end mRNA-seq with WT, Esr1 over-expressing (CERM, tetracycline-operator(tet-op)-Esr1MMTV-rtTA), CYP19A1 over-expressing (AROM, tet-op-CYP19A1MMTV-rtTA) and Brca1 KO (BRCA, Brca1fl11/fl11/MMTV-Cre/p53+/- ) mice
Project description:Biopsies were collected from post-menopausal women with ER+ HER2- breast cancer who were subsequently treated with either letrozole or letrozole plus bevacizumab.
Project description:KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptorpositive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level.