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Genes differentailly expressed in organ-specific metastatic cells derived from MDA-MB-231 breast cancer cell line

ABSTRACT: Breast cancer metastasizes to bone, visceral organs, and/or brain depending on the subtypes. Various cell line models have been used to develop gene expression signatures unique to cancer cells that have metastasized to specific organs, although these efforts were not in a uniform setting. In this study, we compared gene expression pattern in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung metastasis (LMD-231), bone metastasis (BMD-231), adrenal metastasis (ADMD-231) and brain metastasis (231-BR) variants grown under the same growth condition. When gene expression differences between metasteses (p value of <0.01) were compared, 231-BR cells showed the highest gene expression difference (633 genes) followed by ADMD-231 (196 genes), LMD-231 (79 genes), and BMD-231 cells (60 genes) compared with other metastatic cells. 231-BR cells specifically overexpressed neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1 by more than five fold compared with cells isolated from other sites of metastasis. Ingenuity pathway analysis of differentially expressed genes revealed activation of pathways that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR cells, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-κB signaling pathway activation was common to all metastatic cells except BMD-231.To test this possibility, we compared gene expression pattern in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung-metastasis (LMD-231), bone-metastasis (BMD-231), adrenal-metastasis (ADMD-231) and brain-metastasis (231-BR) variants. Between metastatic cells, 231-BR cells showed the highest gene expression difference followed by ADMD-231, LMD-231, and BMD-231 cells. 231-BR cells specifically overexpressed neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1. pathways that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR cells, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-κB signaling pathway activation was common to all metastatic cells except BMD-231.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66495 | GEO | 2015/04/01

SECONDARY ACCESSION(S): PRJNA277145

REPOSITORIES: GEO

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Project description:Breast cancer metastasizes to bone, visceral organs, and/or brain depending on the subtypes. Various cell line models have been used to develop gene expression signatures unique to cancer cells that have metastasized to specific organs, although these efforts were not in a uniform setting. In this study, we compared gene expression pattern in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung metastasis (LMD-231), bone metastasis (BMD-231), adrenal metastasis (ADMD-231) and brain metastasis (231-BR) variants grown under the same growth condition. When gene expression differences between metasteses (p value of <0.01) were compared, 231-BR cells showed the highest gene expression difference (633 genes) followed by ADMD-231 (196 genes), LMD-231 (79 genes), and BMD-231 cells (60 genes) compared with other metastatic cells. 231-BR cells specifically overexpressed neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1 by more than five fold compared with cells isolated from other sites of metastasis. Ingenuity pathway analysis of differentially expressed genes revealed activation of pathways that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR cells, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-κB signaling pathway activation was common to all metastatic cells except BMD-231.To test this possibility, we compared gene expression pattern in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung-metastasis (LMD-231), bone-metastasis (BMD-231), adrenal-metastasis (ADMD-231) and brain-metastasis (231-BR) variants. Between metastatic cells, 231-BR cells showed the highest gene expression difference followed by ADMD-231, LMD-231, and BMD-231 cells. 231-BR cells specifically overexpressed neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1. pathways that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR cells, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-κB signaling pathway activation was common to all metastatic cells except BMD-231. Cells were maintained in MEM with 10% fetal calf serum. RNA was prepared exponentially growing cells using RNeasy kit (Qiagen, Valencia, CA, USA) Microarray with biological triplicates was performed using Illumina HumanHT-12 V4 expression beadchip. Probe profile data was imported into partek genomics suite. Genes that showed statistically insignificant signals in majority of samples were removed from the microarray data, and only those probes that showed statistically significant signal in at least half of samples of at least one group were retained. Differential expression analysis was performed using ANOVA.

Project description:Introduction: The prognosis for patients with breast tumor metastases to brain is extremely poor. Identification of prognostic molecular markers of the metastatic process is critical for designing therapeutic modalities for reducing the occurrence of metastasis. Although ubiquitously present in most human organs, calcium-activated potassium (BK) channel is significantly upregulated in breast cancer cells. In this study we investigated the role of KCNMA1 gene, which encodes α subunit of KCa channels (BK channels) in breast cancer metastasis and invasion. Methods: We performed Global exon array to study the expression of KCNMA1 in metastatic breast cancer in brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of α subunit of KCa channel protein in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells (MCF-10A), non-metastatic breast cancer (MCF-7), non-brain metastatic breast cancer cells (MDA-MB-231), and brain-specific metastatic breast cancer cells (MDA-MB-361) to study whether KCa channel inhibition attenuates breast tumor invasion and metastasis using KCNMA1 knockdown with siRNA and biochemical inhibition with IBTX (Iberiotoxin). Results: The Global exon array and RT-PCR showed higher KCNMA1 expression in metastatic breast cancer in brain compared to metastatic breast cancers in other organs. Our results clearly show that metastatic breast cancer cells exhibit increased BK channel activity, leading to greater invasiveness and transendothelial migration, both of which could be attenuated by blocking KCNMA1. Conclusion: Determining the relative abundance of BK channel over expression in breast cancer metastatic to brain and the mechanism of its action in brain metastasis will provide a unique opportunity to identify and differentiate between low grade breast tumors that are at high risk for metastasis from those at low risk for metastasis. This distinction would in turn allow for the appropriate and efficient application of effective treatments while sparing patients with low risk for metastasis from the toxic side effects of chemotherapy.

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Genes differentailly expressed in organ-specific metastatic cells derived from MDA-MB-231 breast cancer cell line

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