TGFβ-dependent induction of interleukin-11 and interleukin-8 involves SMAD and p38 MAPK pathways in breast tumor models with varied bone metastases potential

Gupta, Janhavi; Robbins, John; Jilling, Tamás; Seth, Prem

doi:10.4161/cbt.11.3.14096

Cited by 45 publications

(39 citation statements)

References 22 publications

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“…This is also consistent with previous reports showing that TGF-βRII can activate MAPK (38) and PI3K (39) independently of TGF-βR1 and that RNA interference of p38 MAPK abrogates IL-8 expression in a mouse model of MDA231 bone metastasis (40). Further, TGF-β can still induce p38MAPK-dependent invasion and IL-11 secretion in SMAD4-null MDA468 cells (40). In data not shown herein, treatment with LY2157299 abrogated paclitaxel-induced enrichment of CSCs in MDA468 cells.…”

Section: Methodssupporting

confidence: 81%

“…Since this antibody blocks access of endogenous ligands to TGF-βRII (12), this result implies that chemotherapy-mediated induction of IL-8 follows autocrine activation of the type II receptor. This is also consistent with previous reports showing that TGF-βRII can activate MAPK (38) and PI3K (39) independently of TGF-βR1 and that RNA interference of p38 MAPK abrogates IL-8 expression in a mouse model of MDA231 bone metastasis (40). Further, TGF-β can still induce p38MAPK-dependent invasion and IL-11 secretion in SMAD4-null MDA468 cells (40).…”

Section: Methodssupporting

confidence: 81%

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TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer

Bhola¹,

Balko²,

Dugger³

et al. 2013

J. Clin. Invest.

526

487

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After an initial response to chemotherapy, many patients with triple-negative breast cancer (TNBC) have recurrence of drug-resistant metastatic disease. Studies with TNBC cells suggest that chemotherapy-resistant populations of cancer stem-like cells (CSCs) with self-renewing and tumor-initiating capacities are responsible for these relapses. TGF-β has been shown to increase stem-like properties in human breast cancer cells. We analyzed RNA expression in matched pairs of primary breast cancer biopsies before and after chemotherapy. Biopsies after chemotherapy displayed increased RNA transcripts of genes associated with CSCs and TGF-β signaling. In TNBC cell lines and mouse xenografts, the chemotherapeutic drug paclitaxel increased autocrine TGF-β signaling and IL-8 expression and enriched for CSCs, as indicated by mammosphere formation and CSC markers. The TGF-β type I receptor kinase inhibitor LY2157299, a neutralizing TGF-β type II receptor antibody, and SMAD4 siRNA all blocked paclitaxel-induced IL8 transcription and CSC expansion. Moreover, treatment of TNBC xenografts with LY2157299 prevented reestablishment of tumors after paclitaxel treatment. These data suggest that chemotherapy-induced TGF-β signaling enhances tumor recurrence through IL-8-dependent expansion of CSCs and that TGF-β pathway inhibitors prevent the development of drug-resistant CSCs. These findings support testing a combination of TGF-β inhibitors and anticancer chemotherapy in patients with TNBC.

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Section: Methodssupporting

confidence: 81%

Section: Methodssupporting

confidence: 81%

TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer

Bhola¹,

Balko²,

Dugger³

et al. 2013

J. Clin. Invest.

526

487

View full text Add to dashboard Cite

show abstract

“…In addition, IL-11 expression is associated with poor survival in hepatocellular carcinoma (23) and has been associated with an aggressive phenotype and poor prognosis in gastric adenocarcinoma (24). Moreover, IL-11 has been shown to be expressed in metastasis of solid tumors (25), and it increases metastatic potential in breast cancer, endometrial carcinoma, and chondrosarcoma (26)(27)(28). However, whether and by what mechansim(s) IL-11 might contribute to tumor progression are not known.…”

Section: Introductionmentioning

confidence: 99%

Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells

Onnis

Fer²,

Rapisarda³

et al. 2013

J. Clin. Invest.

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IL-11 and its receptor, IL-11Ra, are expressed in human cancers; however, the functional role of IL-11 in tumor progression is not known. We found that IL11 is a hypoxia-inducible, VHL-regulated gene in human cancer cells and that expression of IL11 mRNA was dependent, at least in part, on HIF-1. A cooperative interaction between HIF-1 and AP-1 mediated transcriptional activation of the IL11 promoter. Additionally, we found that human cancer cells expressed a functional IL-11Ra subunit, which triggered signal transduction either by exogenous recombinant human IL-11 or by autocrine production of IL-11 in cells cultured under hypoxic conditions. Silencing of IL11 dramatically abrogated the ability of hypoxia to increase anchorage-independent growth and significantly reduced tumor growth in xenograft models. Notably, these results were phenocopied by partial knockdown of STAT1 in a human prostate cancer cell line (PC3), suggesting that this pathway may play an important role in mediating the effects of IL-11 under hypoxic conditions. In conclusion, these results identify IL11 as an oxygen-and VHL-regulated gene and provide evidence of a pathway "hijacked" by hypoxic cancer cells that may contribute to tumor progression.

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“…Because TGF-b induction of IL-11 has been shown to be mediated by the Smad pathway (13,14), we tested whether silencing of HS6ST2 affected Smad2/3/4-mediated transcriptional activity. This was done using a luciferase reporter construct containing a functional Smad-binding site.…”

Section: Hs6st2 Silencing Inhibits Smad Signalingmentioning

confidence: 99%

Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

Pollari

Käkönen

Mohammad

et al. 2012

Molecular Cancer Research

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TGF-b regulates several steps in cancer metastasis, including the establishment of bone metastatic lesions. TGF-b is released from bone during osteoclastic bone resorption and it stimulates breast cancer cells to produce osteolytic factors such as interleukin 11 (IL-11). We conducted a cell-based siRNA screen and identified heparan sulfate 6-Osulfotransferase 2 (HS6ST2) as a critical gene for TGF-b-induced IL-11 production in highly bone metastatic MDA-MB-231(SA) breast cancer cells. HS6ST2 attaches sulfate groups to glucosamine residues in heparan sulfate glycosaminoglycans. We subsequently showed how heparin and a high-molecular-weight Escherichia coli K5-derived heparin-like polysaccharide (K5-NSOS) inhibited TGF-b-induced IL-11 production in MDA-MB-231 (SA) cells. In addition, K5-NSOS inhibited bone resorption activity of human osteoclasts in vitro. We evaluated the therapeutic potential of K5-NSOS and fragmin in a mouse model of breast cancer bone metastasis. MDA-MB-231 (SA) cells were inoculated into the left cardiac ventricle of athymic nude mice which were treated with fragmin, K5-NSOS, or vehicle once a day for four weeks. Both heparin-like glycosaminoglycans inhibited weight reduction, decreased osteolytic lesion area, and reduced tumor burden in bone. In conclusion, our data imply novel mechanisms involved in TGF-b induction and support the critical role of heparan sulfate glycosaminoglycans in cancer metastasis as well as indicate that K5-NSOS is a potential antimetastatic and antiresorptive agent for cancer therapy. This study illustrates the potential to translate in vitro siRNA screening results toward in vivo therapeutic concepts. Mol Cancer Res; 10(5); 597-604. Ó2012 AACR.

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TGFβ-dependent induction of interleukin-11 and interleukin-8 involves SMAD and p38 MAPK pathways in breast tumor models with varied bone metastases potential

Cited by 45 publications

References 22 publications

TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer

TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer

Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells

Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

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