Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human MCF7 wt and MCF7/HER2-18 xenografts

ABSTRACT: To investigate molecular mechanisms of resistance, we used two different in vivo xenograft models of estrogen receptor-positive (ER+) breast cancer, with or without HER2 over-expression (MCF7/HER2-18 and MCF7 wt, respectively). Mice with established tumors were assigned to the following treatment groups: continued estrogen supplementation (E2), estrogen deprivation (ED), ED plus tamoxifen (Tam), all with or without the EGFR tyrosine kinase inhibitor gefinitinib (G). Another group received ED plus the antiestrogen fulvestrant (MCF7 wt only). Tumors with acquired or de novo resistance to these endocrine therapies were profiled for mRNA expression using Affymetrix Genechip arrays. This SuperSeries is composed of the following subset Series:; GSE8139: Expression data from MCF7/HER2-18 xenografts; GSE8140: Expression data from MCF7 wt xenografts Experiment Overall Design: MCF7 xenografts were established in ovariectomized five to six week-old nu/nu athymic nude mice supplemented with 0.25 mg 21 day release estrogen pellets by inoculating subcutaneously (s.c.) 5E-6 cells. When tumors reached the size of 150-200 mm3 (3-5 weeks), the animals were randomly allocated to continued estrogen (E2), continued estrogen with gefitinib (E2+G; 100mg/kg, 5 days/week), estrogen withdrawal alone (ED; by removal of the estrogen pellets), and estrogen withdrawal plus tamoxifen citrate (Tam; 500 microg/animal s.c. in peanut oil, 5 days/week), with either gefitinib (Tam+G; 100mg/kg, 5 days/week) or vehicle (1% Tween 80) administered via gavage, as well as estrogen withdrawal plus fulvestrant (ICI 182,780) in the MCF7 wt model (Fulv; 5mg/mouse s.c. once weekly), and estrogen withdrawal with gefitinib (ED+G). Tumors were harvested for molecular studies when they became resistant to treatment and reached the size of 1000 mm3 (n=7). Experiment Overall Design: Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: Chad Creighton

PROVIDER: E-GEOD-8141 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Development of resistance to targeted therapies transforms the clinically associated molecular profile subtype of breast tumor xenografts.

Creighton Chad J CJ Massarweh Suleiman S Huang Shixia S Tsimelzon Anna A Hilsenbeck Susan G SG Osborne C Kent CK Shou Jiang J Malorni Luca L Schiff Rachel R

Cancer research 20080901 18

The effectiveness of therapies targeting specific pathways in breast cancer, such as the estrogen receptor or HER2, is limited because many tumors manifest resistance, either de novo or acquired, during the course of treatment. To investigate molecular mechanisms of resistance, we used two xenograft models of estrogen receptor-positive (ER+) breast cancer, one with and one without HER2 overexpression (MCF7/HER2-18 and MCF7 wt, respectively). Mice with established tumors were assigned to the foll ...[more]

PMID: 18794137

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Project description:Targeting the estrogen signaling pathway has proved to be of great value in the treatment of human breast cancer. Tamoxifen, a selective estrogen receptor modulator (SERM), is the most widely used antiestrogen. However, only 40-50% of patients with estrogen receptor (ER) positive breast cancer benefit from tamoxifen treatment and 30-50% acquire resistance and the disease progresses. Continuous treatment with conventional therapy may contribute to cancer progression in recurring cancers through the accumulation of drug resistant cancer progenitors. We found that MCF7 tamoxifen-resistant (TAM-R) cells possess a significantly higher proportion of cancer progenitor cells than tamoxifen-sensitive MCF7 cells. Our results indicate that the chemokine receptor CXCR4 plays an important role in the maintenance of cancer progenitors in a tamoxifen-resistant cell line and downregulation of CXCR4 signaling by small molecule antagonists specifically inhibits growth of a stem-like cell population in tamoxifen-resistant tumors both in vitro and in vivo. Whole genome gene expression analysis revealed aryl hydrocarbon receptor (AhR) signaling as one of the top networks that is differentially regulated in MCF7(TAM-R) xenograft tumors treated with the CXCR4 antagonist AMD3100 as compared to MCF7 tumors. Further, small molecule antagonists of AhR signaling specifically inhibit the progenitor population in MCF7(TAM-R) cells suggesting that the aryl hydrocarbon receptor could be a putative target for the treatment of tamoxifen-resistant breast cancers. Introduction transplants remains limited by the ability to expand these cells ex vivo. An unbiased screen with primary human HSCs identified a purine derivative, StemRegenin 1 (SR1), that promotes the ex vivo expansion of CD34+ cells. Culture of HSCs with SR1 led to a 50-fold increase in cells expressing CD34 and a 17-fold increase in cells that retain the ability to engraft immunodeficient mice. Mechanistic studies show that SR1 acts by antagonizing the aryl hydrocarbon receptor (AHR). The identification of SR1 and AHR modulation as a means to induce ex vivo HSC expansion should facilitate the clinical use of HSC therapy. Tamoxifen resistant or sensitive xenografts; mice treated with estrogen and/or CXCR4 modulators

Dataset Information

Transcription profiling of human MCF7 wt and MCF7/HER2-18 xenografts

Publications

Development of resistance to targeted therapies transforms the clinically associated molecular profile subtype of breast tumor xenografts.

Similar Datasets

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