Transforming growth factor-β1 is a new form of tumor suppressor with true haploid insufficiency

Tang, Binwu; Böttinger, Erwin P.; Jakowlew, Sonia B.; Bagnall, Kerri; Mariano, Jennifer; Anver, Miriam R.; Letterio, John J.; Wakefield, Lalage M.

doi:10.1038/nm0798-802

Cited by 290 publications

(222 citation statements)

References 35 publications

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“…Importantly, there remains a significant reduction in the ability of breast cancer cells to establish or grow in TGF-b1 þ /À; RAG2À/À tibiae compared with wild-type controls. This dramatic effect in TGF-b1 þ /À; RAG2 À/À mice may reflect the fact that TGF-b1 protein levels have been found to be reduced up to 60-90% of the levels observed in wild-type mice without a concomitant upregulation of TGF-b2 or TGF-b3 (Tang et al, 1998). Thus, our results show that the reduced levels of TGF-b1 can have a profound effect on the ability of breast cancer cells to establish or grow in bone.…”

Section: Discussionmentioning

confidence: 94%

“…Approximately 72% of the tibial injections in TGF-b1 þ / þ ; RAG2À/À gave rise to osteolytic lesions compared with only 44% in TGF-b1 þ /À; RAG2À/À mice and 33% in TGF-b1À/À; RAG2À/À animals ( Figure 3b). The dramatic effect observed in TGF-b1 þ /À; RAG2À/À mice most likely reflects the fact that TGF-b1 protein levels are reduced up to 60-90% of the levels observed in wild-type mice (Tang et al, 1998). Interestingly, bioluminescence imaging showed that MDA-MB-231 breast cancer cells capable of establishing themselves in TGF-b1 þ / þ ; RAG2À/À, TGF-b1 þ /À; RAG2À/À and TGF-b1À/À; RAG2À/À mice grew out at similar rates ( Figure 4a) and induced similar degrees of osteolytic bone destruction (Figure 4b).…”

Section: Tgf-b-neutralizing Ligand Trap Impairs Signaling Induced By mentioning

confidence: 97%

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Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

Mourskaia

Dong

et al. 2008

Oncogene

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Transforming growth factor (TGF)-b signaling is a potent modulator of the invasive and metastatic behavior of breast cancer cells. Indeed, breast tumor responsiveness to TGF-b is important for the development of osteolytic bone metastases. However, the specific TGF-b isoforms that promote breast cancer outgrowth in bone is unknown. We demonstrate that expression of a TGF-b ligand trap, which neutralizes TGF-b1 and TGF-b3, in MDA-MB-231 breast cancer cells diminished their outgrowth in bone and reduced the severity of osteolytic lesion formation when compared with controls. We further show that a reduction or loss of TGF-b1 expression within the bone microenvironment of TGF-b1 þ /À and TGF-b1À/À mice significantly reduced the incidence of breast tumor outgrowth compared with wild-type animals. Interestingly, those tumors capable of growing within the tibiae of TGF-b1-deficient mice had upregulated expression of all three TGF-b isoforms. Finally, breast cancer cells expressing the TGF-b ligand trap showed a pronounced reduction in their ability to form osteolytic lesions when injected into the tibiae of TGF-b1 þ /À mice. Thus, our studies show that both host-and tumor-derived TGF-b expression plays a critical role during the establishment and outgrowth of breast cancer cells in bone.

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Section: Discussionmentioning

confidence: 94%

Section: Tgf-b-neutralizing Ligand Trap Impairs Signaling Induced By mentioning

confidence: 97%

Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

Mourskaia

Dong

et al. 2008

Oncogene

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“…Accordingly, TGF-b1 þ /À mutant mice are significantly more susceptible (3.2-fold) to diethylnitrosamine and phenobarbital after 9 months of treatment compared with wild types (Tang et al, 1998). In addition, transgenic mice overexpressing a dominant negative TBRII exhibit significant increase in incidence, size and multiplicity of preneoplastic lesions and of HCCs (Tang et al, 1998;Kanzler et al, 2001). Also, in chronic hepatitis C infection, HCV-derived core protein associates with the Smad3 MH1 domain inhibiting its DNA-binding activity (Pavio et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Given its antiproliferative role in various epithelial cells as well as in liver, the TGF-b signaling likely suppresses hepatocellular carcinogenesis. Accordingly, TGF-b1 þ /À mutant mice are significantly more susceptible (3.2-fold) to diethylnitrosamine and phenobarbital after 9 months of treatment compared with wild types (Tang et al, 1998). In addition, transgenic mice overexpressing a dominant negative TBRII exhibit significant increase in incidence, size and multiplicity of preneoplastic lesions and of HCCs (Tang et al, 1998;Kanzler et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

et al. 2007

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Transforming growth factor-b (TGF-b) signaling members, TGF-b receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf þ /À mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (Po0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-b signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.

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“…Targeted deletion of TGF-b1 gene predisposes mice to the development of squamous cell carcinoma (Glick et al, 1994). Hemizygous or homozygous Tgfb1-null animals show increased incidence of chemically or spontaneously induced tumors (Tang et al, 1998). Several components of the TGF-b signaling pathway have been found to act as tumor suppressors.…”

Section: Introductionmentioning

confidence: 99%

Synergistic effect between EGF and TGF-β1 in inducing oncogenic properties of intestinal epithelial cells

et al. 2007

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Transforming growth factor (TGF)-b1 has a biphasic effect on rat intestinal epithelial (RIE) cells. By itself, TGF-b1 functions as a tumor suppressor by inhibiting the growth, migration and invasion of RIE cells. We show in this study that in conjunction with epidermal growth factor (EGF), TGF-b1 helped to augment migration, invasion and anchorage-independent growth (AIG) compared to that by EGF alone. EGF plus TGF-b1 induced a dramatic morphological change characteristic of epithelial-mesenchymal transition (EMT). The mechanism for this enhanced effect of TGF-b1 and EGF on oncogenic properties was explored by analysis of EGF-and TGF-b1-mediated signaling pathways and complementary DNA arrays. TGF-b1 augmented EGF-mediated signaling of mitogen-activated protein kinase (MAPK) and AKT by enhancing and prolonging the activation of the former and prolonging the activation of the latter. Inhibition of MAPK, but not phosphoinositide-3 kinase (PI3K), abolished TGF-b1 plus EGF-induced EMT and downregulation of E-cadherin at mRNA and protein levels. By contrast, cell migration and invasion were sensitive to inhibition of either MAPK or PI3 kinase. TGF-b1 plus EGF-induced AIG was significantly more resistant to inhibition of PI3K and MAPK compared to that induced by EGF alone. EGF and TGF-b1 synergistically induced the expression of a series of proteases including matrix metalloproteinase (MMP) 1 (collagenase), MMP3, MMP9, MMP10, MMP14 and cathepsin. Among them, the expression of MMP1, MMP3, MMP9 and MMP10 was MAPK dependent. Inhibition of the MMPs or cathepsin significantly blocked EGF plus TGF-b1-induced invasion, but had no effect on colony formation.Phospholipase C (PLC) and Cox2 induced by EGF plus TGF-b1 also played a significant role in invasion, whereas PLC was also important for colony formation. Our study reveals specific signaling functions and induction of genes differentially required for enhanced effect of EGF-and TGF-b1-induced oncogenic properties, and helps to explain the tumor-promoting effect of TGF-b1 in human cancer with elevated expression or activation of TGF-b1 and receptor protein tyrosine kinases.

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Transforming growth factor-β1 is a new form of tumor suppressor with true haploid insufficiency

Cited by 290 publications

References 35 publications

Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

Synergistic effect between EGF and TGF-β1 in inducing oncogenic properties of intestinal epithelial cells

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