Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells

Sirkku Pollari (Corresponding Author), Suvi-Katri Leivonen, Merja Perälä, Vidal Fey, Sanna-Maria Käkönen, Olli Kallioniemi

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor β (TGF-β) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast cancer cells. IL-11 in turn increases osteolysis by stimulating osteoclast function, launching a vicious cycle of cancer growth and bone destruction. We aimed to identify and functionally characterize microRNAs (miRNAs) that mediate the bone metastatic process, focusing on miRNAs that regulate the TGF-β induction of IL-11. First, we profiled the expression of 455 miRNAs in a highly bone metastatic MDA-MB-231(SA) variant as compared to the parental MDA-MB-231 breast cancer cell line and found 16 miRNAs (3.5%) having a >3-fold expression difference between the two cell types. We then applied a cell-based overexpression screen with Pre-miRNA constructs to functionally identify miRNAs regulating TGF-β-induced IL-11 production. This analysis pinpointed miR-204, miR-211, and miR-379 as such key regulators. These miRNAs were shown to directly target IL11 by binding to its 3′ UTR. MiR-379 also inhibited Smad2/3/4-mediated transcriptional activity. Gene expression analysis of miR-204 and miR-379-transfected cells indicated that these miRNAs downregulated the expression of several genes involved in TGF-β signaling, including prostaglandin-endoperoxide synthase 2 (PTGS2). In addition, there was a significant correlation between the genes downregulated by miR-379 and a set of genes upregulated in basal subtype of breast cancer. Taken together, the functional evidence and clinical correlations imply novel mechanistic links between miRNAs and the key steps in the bone metastatic process in breast cancer, with potential clinical relevance.
Original languageEnglish
Article numbere37361
Number of pages9
JournalPLoS ONE
Volume7
Issue number5
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

Fingerprint

interleukin-11
Interleukin-11
transforming growth factors
Transforming Growth Factors
MicroRNAs
microRNA
breast neoplasms
Bone
Cells
bones
Breast Neoplasms
Bone and Bones
Bone Neoplasms
Genes
Down-Regulation
cells
Gene Expression
neoplasm cells
gene expression
Osteolysis

Cite this

Pollari, S., Leivonen, S-K., Perälä, M., Fey, V., Käkönen, S-M., & Kallioniemi, O. (2012). Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells. PLoS ONE, 7(5), [e37361]. https://doi.org/10.1371/journal.pone.0037361
Pollari, Sirkku ; Leivonen, Suvi-Katri ; Perälä, Merja ; Fey, Vidal ; Käkönen, Sanna-Maria ; Kallioniemi, Olli. / Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells. In: PLoS ONE. 2012 ; Vol. 7, No. 5.
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abstract = "Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor β (TGF-β) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast cancer cells. IL-11 in turn increases osteolysis by stimulating osteoclast function, launching a vicious cycle of cancer growth and bone destruction. We aimed to identify and functionally characterize microRNAs (miRNAs) that mediate the bone metastatic process, focusing on miRNAs that regulate the TGF-β induction of IL-11. First, we profiled the expression of 455 miRNAs in a highly bone metastatic MDA-MB-231(SA) variant as compared to the parental MDA-MB-231 breast cancer cell line and found 16 miRNAs (3.5{\%}) having a >3-fold expression difference between the two cell types. We then applied a cell-based overexpression screen with Pre-miRNA constructs to functionally identify miRNAs regulating TGF-β-induced IL-11 production. This analysis pinpointed miR-204, miR-211, and miR-379 as such key regulators. These miRNAs were shown to directly target IL11 by binding to its 3′ UTR. MiR-379 also inhibited Smad2/3/4-mediated transcriptional activity. Gene expression analysis of miR-204 and miR-379-transfected cells indicated that these miRNAs downregulated the expression of several genes involved in TGF-β signaling, including prostaglandin-endoperoxide synthase 2 (PTGS2). In addition, there was a significant correlation between the genes downregulated by miR-379 and a set of genes upregulated in basal subtype of breast cancer. Taken together, the functional evidence and clinical correlations imply novel mechanistic links between miRNAs and the key steps in the bone metastatic process in breast cancer, with potential clinical relevance.",
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Pollari, S, Leivonen, S-K, Perälä, M, Fey, V, Käkönen, S-M & Kallioniemi, O 2012, 'Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells', PLoS ONE, vol. 7, no. 5, e37361. https://doi.org/10.1371/journal.pone.0037361

Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells. / Pollari, Sirkku (Corresponding Author); Leivonen, Suvi-Katri; Perälä, Merja; Fey, Vidal; Käkönen, Sanna-Maria; Kallioniemi, Olli.

In: PLoS ONE, Vol. 7, No. 5, e37361, 2012.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells

AU - Pollari, Sirkku

AU - Leivonen, Suvi-Katri

AU - Perälä, Merja

AU - Fey, Vidal

AU - Käkönen, Sanna-Maria

AU - Kallioniemi, Olli

PY - 2012

Y1 - 2012

N2 - Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor β (TGF-β) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast cancer cells. IL-11 in turn increases osteolysis by stimulating osteoclast function, launching a vicious cycle of cancer growth and bone destruction. We aimed to identify and functionally characterize microRNAs (miRNAs) that mediate the bone metastatic process, focusing on miRNAs that regulate the TGF-β induction of IL-11. First, we profiled the expression of 455 miRNAs in a highly bone metastatic MDA-MB-231(SA) variant as compared to the parental MDA-MB-231 breast cancer cell line and found 16 miRNAs (3.5%) having a >3-fold expression difference between the two cell types. We then applied a cell-based overexpression screen with Pre-miRNA constructs to functionally identify miRNAs regulating TGF-β-induced IL-11 production. This analysis pinpointed miR-204, miR-211, and miR-379 as such key regulators. These miRNAs were shown to directly target IL11 by binding to its 3′ UTR. MiR-379 also inhibited Smad2/3/4-mediated transcriptional activity. Gene expression analysis of miR-204 and miR-379-transfected cells indicated that these miRNAs downregulated the expression of several genes involved in TGF-β signaling, including prostaglandin-endoperoxide synthase 2 (PTGS2). In addition, there was a significant correlation between the genes downregulated by miR-379 and a set of genes upregulated in basal subtype of breast cancer. Taken together, the functional evidence and clinical correlations imply novel mechanistic links between miRNAs and the key steps in the bone metastatic process in breast cancer, with potential clinical relevance.

AB - Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor β (TGF-β) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast cancer cells. IL-11 in turn increases osteolysis by stimulating osteoclast function, launching a vicious cycle of cancer growth and bone destruction. We aimed to identify and functionally characterize microRNAs (miRNAs) that mediate the bone metastatic process, focusing on miRNAs that regulate the TGF-β induction of IL-11. First, we profiled the expression of 455 miRNAs in a highly bone metastatic MDA-MB-231(SA) variant as compared to the parental MDA-MB-231 breast cancer cell line and found 16 miRNAs (3.5%) having a >3-fold expression difference between the two cell types. We then applied a cell-based overexpression screen with Pre-miRNA constructs to functionally identify miRNAs regulating TGF-β-induced IL-11 production. This analysis pinpointed miR-204, miR-211, and miR-379 as such key regulators. These miRNAs were shown to directly target IL11 by binding to its 3′ UTR. MiR-379 also inhibited Smad2/3/4-mediated transcriptional activity. Gene expression analysis of miR-204 and miR-379-transfected cells indicated that these miRNAs downregulated the expression of several genes involved in TGF-β signaling, including prostaglandin-endoperoxide synthase 2 (PTGS2). In addition, there was a significant correlation between the genes downregulated by miR-379 and a set of genes upregulated in basal subtype of breast cancer. Taken together, the functional evidence and clinical correlations imply novel mechanistic links between miRNAs and the key steps in the bone metastatic process in breast cancer, with potential clinical relevance.

U2 - 10.1371/journal.pone.0037361

DO - 10.1371/journal.pone.0037361

M3 - Article

VL - 7

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 5

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