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Leptin is Implicated in Aromatase Inhibitor Resistance in Breast Cancer Cells

ABSTRACT: Leptin is Implicated in Aromatase Inhibitor Resistance in Breast Cancer Cells

PROVIDER: PRJEB37042 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR3971813_1.fastq.gz	Fastqsanger.gz
	ERR3971813_2.fastq.gz	Fastqsanger.gz
	ERR3971814_1.fastq.gz	Fastqsanger.gz
	ERR3971814_2.fastq.gz	Fastqsanger.gz
	ERR3971815_1.fastq.gz	Fastqsanger.gz

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Leptin is Implicated in Aromatase Inhibitor Resistance in Breast Cancer Cells

Project description:Obesity represents a risk factor for breast cancer development and therapy resistance, but the molecular players underling these links are unclear. Here, we identify a role for the obesity-cytokine leptin in sustaining aromatase inhibitor (AI) resistant growth and progression in breast cancer. Using as a cellular model MCF-7 breast cancer cells surviving long-term to the AI treatment Anastrozole (AnaR) and Ana-sensitive counterparts, we found that AnaR cells expressed higher levels of leptin and its receptors (ObR) along with a constitutive activation of downstream effectors. Accordingly, leptin signaling inhibition reduced only AnaR cell growth and motility, highlighting the existence of an autocrine loop in mechanisms governing drug-resistant phenotype. In agreement with ObR overexpression, increasing doses of leptin were able to stimulate at a greater extent growth and migration in AnaR than sensitive cells. Moreover, leptin contributed to an enhanced crosstalk between AnaR cells and macrophages within tumor microenvironment. Indeed, AnaR through leptin secretion modulated macrophage profiles and increased macrophage motility through CXCR4 signaling, as evidenced by RNA-sequencing, realtime-PCR and immunoblotting. Reciprocally, activated macrophages increased AnaR cell growth and motility in coculture systems.

2022-03-04 | E-MTAB-8843 | biostudies-arrayexpress

GDNF-RET signaling as a target in aromatase inhibitor resistant breast cancers

Project description:Understanding the complex molecular mechanisms underlying resistance to endocrine therapy is a major challenge in the treatment of estrogen receptor-positive (ER+) breast cancers. We have previously demonstrated that glial cell line-derived neurotrophic factor (GDNF) signaling via the receptor tyrosine kinase RET promotes estrogen independent activation of ER. Here we have addressed the relevance of GDNF-RET signaling in response to aromatase inhibitor treatment and explored the efficacy of using RET inhibitors in breast cancer models of aromatase inhibitor response and resistance. A GDNF-response gene set, identified from gene expression profiling, was demonstrated to be an independent prognostic marker of poor patient outcome and, importantly, to be predictive of poor response to aromatase inhibitor treatment and development of resistance. The relevance of these findings was validated first by demonstrating an association of RET protein expression in an independent cohort of aromatase inhibitor resistant patient samples. Second, in in vitro models, GDNF-mediated RET signaling was demonstrated to enhance the survival of aromatase inhibitor resistant cells and to increase resistance in aromatase inhibitor sensitive cells. These effects could be reversed by targeting GDNF/RET signaling with the RET selective inhibitor NVP-BBT594 thus identifying GDNF-RET signaling as a potential therapeutic target, particularly in breast cancers resistant to aromatase inhibitors.<br>MCF7 cells were E2-deprived by culturing in phenol red-free RPMI 1640 supplemented with 10% DCC for 3 days and then serum-starved overnight in the presence or absence of fulvestrant (ICI182,780) (100 nM). The following day, cells were treated with GDNF (20 ng/ml) for 0, 4, 8, 24 and 48 hours in the presence or absence of fulvestrant (ICI182,780) (100 nM).

2013-01-17 | E-MEXP-3662 | biostudies-arrayexpress

Molecular profiling of aromatase inhibitor-treated post-menopausal breast tumors identifies immunerelated correlates of resistance

Project description:To identify in clinical breast cancer those genes and pathways most associated with resistance to aromatase inhibitors by examining the global transcriptional effects of aromatase inhibitor (AI) treatment. Analysis of gene-expression measured in core-cut biopsies at baseline and surgery from patients received 2-week’s presurgical AI revealed: i) the molecular response to AI treatment varies greatly between patients, consistent with the variable clinical benefit from AI treatment; ii) higher baseline expression of an inflammatory signature is associated with poor antiproliferative response, and should be assessed further as a novel biomarker and potential target for AI-treated patients.

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Transcription profiling by array of aromatase-inhibitor-resistant breast cancer cell lines derived from T-47D

2014-04-01 | E-MTAB-1933 | biostudies-arrayexpress

The gene expression of aromatase-inhibitor-resistant cell line

2014-04-01 | GSE51390 | GEO

The gene expression of aromatase-inhibitor-resistant cell line

Project description:To identify the genes which have relation to aromatase-inhibitor-resistance, we compared the gene expression of aromatase-inhibitor-resistant cell, A3, with that of parent cell line, T-47D. Because A3 showed remarkable cell proliferation by 1nM Dihydrotestosterone(DHT), cells were cultured with DHTand bicalutamide for 24h, and total RNA was extracted.

2014-04-01 | E-GEOD-51390 | biostudies-arrayexpress

Global mapping of estrogen receptor and histone modifications in breast tumor samples uncovers distinct patterns for aromatase inhibitor resistance

Project description:ChIP-seq on primary breast cancer tumor samples for Era, H3K4me3, H3K27me3. Patients had a poor or good outcome after aromatase inhibitor treatment. Differential binding patterns between good and poor outcome patients were identified for each marker, predicting response to treatment

2013-12-05 | GSE40867 | GEO

Global mapping of estrogen receptor and histone modifications in breast tumor samples uncovers distinct patterns for aromatase inhibitor resistance

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Pilot metabolomics study of aromatase inhibitor associated arthralgias

Project description:The goal of the experiment is untargeted metabolomic and shotgun lipidomic profiling of serum samples collected from 50 patients before patients initiated therapy with an aromatase inhibitor and again after 3 months of aromatase inhibitor therapy. Half of the patients discontinued treatment within 6 months because of development of arthralgias during therapy and half remained on therapy for at least 24 months without development of significant arthralgias. We plan to analyse effects of AI therapy on metabolomic and lipidomic profiles, and to investigate associations between changes in profiles and development of symptoms.

2017-06-19 | ST000695 | MetabolomicsWorkbench

SNPs of aromatase predict long-term survival and aromatase inhibitor toxicity in patients with early breast cancer: a biomarker analysis of the GIM4 and GIM5 trials

Project description:Aromatase SNPs Predict Survival and aromatase inhibitor Toxicity in Breast Cancer

| PRJEB66306 | ENA