Human breast cancer MDA-MB-231 cells fail to express the neurofibromin protein, lack its type I mRNA isoform and show accumulation of P-MAPK and activated Ras

Ogata, Hideaki; Sato, Hírokazu; Takatsuka, Jun; Luca, Luigi M. De

doi:10.1016/s0304-3835(01)00648-6

Cited by 36 publications

(30 citation statements)

References 21 publications

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“…In agreement with our studies, TAK1 mediates NF-kB regulation by TGF-b1 in hepatocellular carcinoma cells (Arsura et al, 2003). Interestingly, MDA-MB-231 breast cancer cells express high levels of NF-kB transcriptional activity (Sliva et al, 2002) and ca-Ras-ERK signaling (Ogata et al, 2001). Ras-ERK signaling is known to inhibit Smad transcriptional responses (Kretzschmar et al, 1999;Saha et al, 2001).…”

Section: Discussionsupporting

confidence: 88%

TAK1 is required for TGF-β1-mediated regulation of matrix metalloproteinase-9 and metastasis

Safina

et al. 2007

Oncogene

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Transforming growth factor-b 1 (TGF-b1) signaling in tumor cells has been implicated in tumor angiogenesis and metastasis by regulating matrix proteolysis. Although MMP-9/gelatinase-B is an important component of these TGF-b1 responses, the mechanism of its regulation is not well understood. Here, we present evidence that TGF-bactivated protein kinase 1 (TAK1) is critical for TGF-b regulation of MMP-9 and the metastatic potential of breast cancer cell line MDA-MB-231. We found that suppression of TAK1 signaling by dominant-negative (dn) TAK1 or RNA interference (siRNA) reduces expression of MMP-9 and tumor cell invasion, without growth inhibition in cell culture. The orthotopic xenograft studies in SCID mice showed that suppression of TAK1 signaling by dn-TAK1 reduces tumor growth and formation of lung metastases. QJ;Dn-TAK1 reduced the proliferation Ki-67 index and neovasculature of orthotopic xenografts. TAK1-mediated regulation of MMP-9 involves NF-jB signaling. Dn-TAK1 reduces NF-jB transcriptional response and inhibition of NF-jB reduces expression of MMP-9 and activity of the MMP-9 promoter reporter. Together, these findings suggest that TAK1 contributes to TGF-b1-mediated tumor angiogenesis and metastasis via a mechanism involving the TAK1-NF-jB-MMP-9 pathway.

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Section: Discussionsupporting

confidence: 88%

TAK1 is required for TGF-β1-mediated regulation of matrix metalloproteinase-9 and metastasis

Safina

et al. 2007

Oncogene

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“…On the other hand, having any of the other genomic subtypes ( BRAF , RAS , or triple‐wild‐type) did not translate into direct prognostic value in our study. In addition, NF1 aberrations have been linked to more adverse outcomes in other cancer types such as breast cancer and head and neck squamous cell carcinoma (Lenarduzzi et al ., 2013; Ogata et al ., 2001). While being an adverse prognostic marker, a nonsynonymous NF1 mutation can be a favorable treatment‐predictive marker, by virtue of its association with increased mutational load.…”

Section: Discussionmentioning

confidence: 99%

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

et al. 2017

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In general, melanoma can be considered as a UV‐driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen‐activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF,RAS,NF1 mutation or triple‐wild‐type status and correlated with tumor and patient characteristics. We found that the NF1‐mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co‐occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain‐containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1‐mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease‐specific survival, DSS; HR, 1.9; 95% CI, 1.21–3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28–2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.

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“…MDA-MB-231 cells express TGF-␤ receptors, Smad factors, and respond to TGF-␤1 with activation of Smad, p38Mapk signaling, and regulation of gene expression (Bakin et al, 2002; Dumont et al, 2003 and Figure 7c). It has been reported that MDA-MB-231 cells have constitutively active Ras-ERK signaling (Kozma et al, 1987;Ogata et al, 2001), which may through the repression of the ROCK/LIM-kinase/cofilin pathway affect SF formation (Sahai et al, 2001;Pawlak and Helfman, 2002b). Thus, we examined phosphorylation of cofilin, a target of LIM kinase, in MDA-MB-231 cells.…”

Section: Tgf-␤ Does Not Induce Stress Fibers But Stimulates Cell Migrmentioning

confidence: 98%

A Critical Role of Tropomyosins in TGF-β Regulation of the Actin Cytoskeleton and Cell Motility in Epithelial Cells

Bakin

Safina

Rinehart

et al. 2004

MBoC

136

208

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We have investigated transforming growth factor beta (TGF-␤)-mediated induction of actin stress fibers in normal and metastatic epithelial cells. We found that stress fiber formation requires de novo protein synthesis, p38Mapk and Smad signaling. We show that TGF-␤ via Smad and p38Mapk up-regulates expression of actin-binding proteins including high-molecular-weight tropomyosins, ␣-actinin and calponin h2. We demonstrate that, among these proteins, tropomyosins are both necessary and sufficient for TGF-␤ induction of stress fibers. Silencing of tropomyosins with short interfering RNAs (siRNAs) blocks stress fiber assembly, whereas ectopic expression of tropomyosins results in stress fibers. Ectopic-expression and siRNA experiments show that Smads mediate induction of tropomyosins and stress fibers. Interestingly, TGF-␤ induction of stress fibers was not accompanied by changes in the levels of cofilin phosphorylation. TGF-␤ induction of tropomyosins and stress fibers are significantly inhibited by Ras-ERK signaling in metastatic breast cancer cells. Inhibition of the Ras-ERK pathway restores TGF-␤ induction of tropomyosins and stress fibers and thereby reduces cell motility. These results suggest that induction of tropomyosins and stress fibers play an essential role in TGF-␤ control of cell motility, and the loss of this TGF-␤ response is a critical step in the acquisition of metastatic phenotype by tumor cells. INTRODUCTIONThere is solid evidence that the transforming growth factor beta (TGF-␤) signaling pathway is a major cellular growth inhibitory and proapoptotic pathway in epithelial, endothelial, hematopoeitic, and other cell types (Roberts and Wakefield, 2003). However, clinical and experimental studies indicate that metastatic cancers of the breast and other tissues express elevated levels of TGF-␤ that appears to support the metastatic behavior of the tumor cells (Saito et al., 2000;Derynck et al., 2001). This apparent paradox has been associated with a progressive decline in the antitumorigenic function and a gain of protumorigenic activities of TGF-␤, including induction of epithelial to mesenchymal transition (EMT) and tumor cell migration and invasion (Derynck et al., 2001;Wakefield and Roberts, 2002). Oncogenic Ras, Src, and ErbB2 as well as alterations in TGF-␤ signaling mediated by Smads, mitogen-activated protein kinases (Mapks), Rho kinases, and Akt/PKB are thought to contribute to the metastatic phenotype (Derynck and Zhang, 2003;Roberts and Wakefield, 2003).The actin cytoskeleton plays a central role in the regulation of cellular processes linked to metastasis including cell proliferation, apoptosis, anchorage-independent cell growth, and cell migration and invasion (Pawlak and Helfman, 2001;Jaffe and Hall, 2002). TGF-␤ induces a rapid reorganization of the actin cytoskeleton, leading to membrane ruffling at the cell edges in both nontumorigenic and tumorigenic epithelial cells, whereas a prolonged incubation with TGF-␤ results in the formation of stress fibers (Bakin et al., 2002;Edlund et a...

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Human breast cancer MDA-MB-231 cells fail to express the neurofibromin protein, lack its type I mRNA isoform and show accumulation of P-MAPK and activated Ras

Cited by 36 publications

References 21 publications

TAK1 is required for TGF-β1-mediated regulation of matrix metalloproteinase-9 and metastasis

TAK1 is required for TGF-β1-mediated regulation of matrix metalloproteinase-9 and metastasis

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

A Critical Role of Tropomyosins in TGF-β Regulation of the Actin Cytoskeleton and Cell Motility in Epithelial Cells

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