Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8

Wu, Kongming; Katiyar, Sanjay; Li, An‐Ping; Liu, Manran; Ju, Xiaoming; Попов, В. М.; Jiao, Xuanmao; Lisanti, Michael P.; Casola, Antonella; Pestell, Richard G.

doi:10.1073/pnas.0802085105

Cited by 90 publications

(113 citation statements)

References 37 publications

(42 reference statements)

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“…miR-520/373 family directly targets TGFBR2 and their expression inversely correlates in ER À primary breast cancer samples As the pro-inflammatory cytokines IL-6 and IL-8 had previously been reported to modulate cell motility in breast cancer (Wu et al, 2008;Walter et al, 2009;Camp et al, 2011), and NF-kB inhibition in ER À breast cancer cells had been previously reported to abrogate metastasis formation (Park et al, 2007), we hypothesized that miR-373 and miR-520c might have an inhibitory role in cell invasion through deregulation of NF-kB signaling. To investigate this hypothesis, we used the highly invasive and ER À breast carcinoma cell line MDA-MB-231.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, numerous studies have demonstrated that inflammation and inflammatory cells associated with the tumor microenvironment promote tumor growth, angiogenesis and miR-520/373 family modulates NF-jB and TGF-b signaling I Keklikoglou et al metastasis (Hagemann et al, 2004;Cheng et al, 2005Cheng et al, , 2011. Pro-inflammatory cytokines such as IL-6, IL-8 or CXCL1 enable tumor cells to intravasate, thus enhancing their metastatic potential (Wang et al, 2006;Wu et al, 2008;Iliopoulos et al, 2009;Walter et al, 2009;Yu et al, 2010). Moreover, co-cultivation of tumor cells with macrophages has been reported to promote invasiveness of breast cancer cells via TNF-a secretion from the macrophages (Hagemann et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways

et al. 2011

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MicroRNAs (miRNAs) as modulators of gene expression have been described to display both tumor-promoting and tumor-suppressive functions. Although their role has been studied in different tumor types, little is known about how they regulate nuclear factor jB (NF-jB) signaling in breast cancer. Here, we performed an unbiased whole genome miRNA (miRome) screen to identify novel modulators of NF-jB pathway in breast cancer. The screen identified 13 miRNA families whose members induced consistent effects on NF-jB activity. Among those, the miR-520/373 family inhibited NF-jB signaling through direct targeting of RELA and thus strongly reduced expression and secretion of the pro-inflammatory cytokines interleukin (IL)-6 and IL-8. With a combination of in vitro and in vivo approaches, we propose a metastasis-suppressive role of miR-520/373 family. miR520c and miR-373 abrogated both in vitro cell invasion and in vivo intravasation of highly invasive MDA-MB-231 cells. However, knockdown of RELA did not affect their metastatic ability. mRNA profiling of MDA-MB-231 cells on overexpression of miR-520/373 members revealed a strong downregulation of transforming growth factor-b (TGF-b) signaling. Mechanistically, the metastasis-suppressive role of miR-520/373 can be attributed to direct suppression of TGFBR2, as the silencing of TGFBR2 phenocopied the effects of miR-520/373 overexpression on suppression of Smad-dependent expression of the metastasis-promoting genes parathyroid hormone-related protein, plasminogen activator inhibitor-1 and angiopoietin-like 4 as well as tumor cell invasion, in vitro and in vivo. A negative correlation between miR-520c and TGFBR2 expression was observed in estrogen receptor negative (ER À ) breast cancer patients but not in the ER positive (ER þ ) subtype. Remarkably, decreased expression of miR-520c correlated with lymph node metastasis specifically in ER À tumors. Taken together, our findings reveal that miR-520/373 family has a tumor-suppressive role in ER À breast cancer by acting as a link between the NF-jB and TGF-b pathways and may thus contribute to the interplay of tumor progression, metastasis and inflammation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways

et al. 2011

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“…DACH1 is expressed widely in normal adult tissues, and loss of DACH1 expression in human breast and endometrial cancers predicts poor outcome (2,6). DACH1 blocks c-Jun-induced DNA synthesis, reverts the H-Ras and c-Myc-induced oncogenic phenotype in the immortalized human breast epithelial cell line, and inhibits breast tumor metastasis in mice (2,7). Although DACH1 is thought to regulate gene expression by complexing with DNAbinding transcription factors including Six, Jun, and Smad4 (2,(8)(9)(10), no sequence specific DNA binding of DACH1 has been identified so far to our knowledge.…”

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confidence: 99%

Attenuation of Forkhead signaling by the retinal determination factor DACH1

Zhou

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The Drosophila Dachshund (Dac) gene, cloned as a dominant inhibitor of the hyperactive growth factor mutant ellipse, encodes a key component of the retinal determination gene network that governs cell fate. Herein, cyclic amplification and selection of targets identified a DACH1 DNA-binding sequence that resembles the FOX (Forkhead box-containing protein) binding site. Genome-wide in silico promoter analysis of DACH1 binding sites identified gene clusters populating cellular pathways associated with the cell cycle and growth factor signaling. ChIP coupled with high-throughput sequencing mapped DACH1 binding sites to corresponding gene clusters predicted in silico and identified as weight matrix resembling the cyclic amplification and selection of targets-defined sequence. DACH1 antagonized FOXM1 target gene expression, promoter occupancy in the context of local chromatin, and contactindependent growth. Attenuation of FOX function by the cell fate determination pathway has broad implications given the diverse role of FOX proteins in cellular biology and tumorigenesis.cell fate determination | Forkhead protein | transcription factor | tumor suppressor | dachshund homolog 1

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“…DACH1 is expressed widely in normal epithelial tissues, and reduced DACH1 expression predicts poor outcome of breast and endometrial cancer patients (6,9). DACH1 represses TGF-␤ signaling, reduces DNA synthesis, and reverts the tumorigenic phenotypes induced by the oncogenes such as ErbB2, Ras, Src, and Myc in human mammary cell lines (10,11). Reintroduction of DACH1 into breast cancer cells inhibits cellular proliferation and migration/invasion in vitro and tumor initiation and metastasis in vivo (6,11).…”

mentioning

confidence: 99%

“…DACH1 represses TGF-␤ signaling, reduces DNA synthesis, and reverts the tumorigenic phenotypes induced by the oncogenes such as ErbB2, Ras, Src, and Myc in human mammary cell lines (10,11). Reintroduction of DACH1 into breast cancer cells inhibits cellular proliferation and migration/invasion in vitro and tumor initiation and metastasis in vivo (6,11). Crystallization of the human DACH1 Box-N revealed that DACH1 protein forms an ␣/␤ structure resembling a DNA binding motif found in the winged helix/forkhead subgroup of transcriptional factors (12).…”

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confidence: 99%

Transcription Elongation Regulator 1 Is a Co-integrator of the Cell Fate Determination Factor Dachshund Homolog 1

Zhou

Liu

Zhang

et al. 2010

Journal of Biological Chemistry

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Development of the compound eye in Drosophila is tightly regulated by the retinal determination gene network (RDGN), 3 which includes a number of proteins encoded by genes such as twin of eyeless (toy), eyeless (ey), sine oculis (so), and eyes absent (eya) (1). The Dachshund (dac) gene was originally cloned as a dominant inhibitor of ellipse. Genetic deletion of dac causes eye-and wing-specific defects in Drosophila (2). Ectopic expression of the dac gene, alone or together with so and eya, results in ectopic eye formation (3, 4). Vertebrate homologs of ey (Pax6), so (Six), eya (Eya), and dac (DACH1) have been identified, and the human DACH1 (Dach1 in mice) gene encodes a protein composed of two highly conserved domains, dachshund domain 1 (DD1, also known as Box-N) with a predicted helix-turn-helix structure, and dachshund domain 2 (DD2, also known as Box-C). Altered expression of DACH1 has been reported in a variety of human tumors (5-9). DACH1 is expressed widely in normal epithelial tissues, and reduced DACH1 expression predicts poor outcome of breast and endometrial cancer patients (6, 9). DACH1 represses TGF-␤ signaling, reduces DNA synthesis, and reverts the tumorigenic phenotypes induced by the oncogenes such as ErbB2, Ras, Src, and Myc in human mammary cell lines (10, 11). Reintroduction of DACH1 into breast cancer cells inhibits cellular proliferation and migration/invasion in vitro and tumor initiation and metastasis in vivo (6, 11). Crystallization of the human DACH1 Box-N revealed that DACH1 protein forms an ␣/␤ structure resembling a DNA binding motif found in the winged helix/forkhead subgroup of transcriptional factors (12). DACH1 is capable of binding both naked DNA and the chromatin DNA template through its Box-N domain, and the DNA binding is independent of protein association with other DACH1-binding partners (13). A subsequent study using cyclic amplification and selection of targets (CAST) identified a DNA sequence that is specific for DACH1 binding (14). The DACH1 DNA binding sequence resembles a Forkhead protein binding site, and DACH1 competes with FOXM1 from being recruited to the promoter of FOXM1 target genes. The Forkhead Box (FOX) proteins are a family of evolutionarily conserved transcriptional regulators involved in diverse biological processes (15). Deregulation of FOX protein function in human tumorigenesis may occur by alteration in upstream regulators or genetic events such as * This work was supported, in whole or in part, by National Institutes of Health Grants R01CA70896, R01CA75503, and R01CA86072 (to R. G. P.

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Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8

Cited by 90 publications

References 37 publications

MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways

MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways

Attenuation of Forkhead signaling by the retinal determination factor DACH1

Transcription Elongation Regulator 1 Is a Co-integrator of the Cell Fate Determination Factor Dachshund Homolog 1

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