Inhibition of the antiproliferative effect of TGFβ by EGF in primary human ovarian cancer cells

Dunfield, Lesley; Nachtigal, Mark W.

doi:10.1038/sj.onc.1206617

Cited by 29 publications

(24 citation statements)

References 23 publications

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“…It is not due to functional mutations in the TGF-h receptors or Smads, as these occur infrequently (16,35,36). It has also been suggested that other factors, such as epidermal growth factor, abrogate the antiproliferative effect of TGF-h in vivo (37). Our data suggest that it is altered gene expression of TGF-h pathway genes that may account for the resistance of ovarian cancer to the antiproliferative effects of TGF-h. Several other studies have shown that it is not alterations in gene expression of TGF-h pathway genes that are responsible for the resistance of ovarian cancer to the antimitogenic effects of TGF-h but rather blockage of this pathway downstream of the Smad complex formation (12,38).…”

Section: Discussionmentioning

confidence: 60%

Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-β Signaling in Ovarian Cancer

Sunde

Donninger²,

et al. 2006

Cancer Research

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Ovarian cancer is resistant to the antiproliferative effects of transforming growth factor-B (TGF-B); however, the mechanism of this resistance remains unclear. We used oligonucleotide arrays to profile 37 undissected, 68 microdissected advanced-stage, and 14 microdissected early-stage papillary serous cancers to identify signaling pathways involved in ovarian cancer. A total of seven genes involved in TGF-B signaling were identified that had altered expression >1.5-fold (P < 0.001) in the ovarian cancer specimens compared with normal ovarian surface epithelium. The expression of these genes was coordinately altered: genes that inhibit TGF-B signaling (DACH1, BMP7, and EVI1) were up-regulated in advanced-stage ovarian cancers and, conversely, genes that enhance TGF-B signaling (PCAF, TFE3, TGFBRII, and SMAD4) were down-regulated compared with the normal samples. The microarray data for DACH1 and EVI1 were validated using quantitative real-time PCR on 22 microdissected ovarian cancer specimens. The EVI1 gene locus was amplified in 43% of the tumors, and there was a significant correlation (P = 0.029) between gene copy number and EVI1 gene expression. No amplification at the DACH1 locus was found in any of the samples. DACH1 and EVI1 inhibited TGF-B signaling in immortalized normal ovarian epithelial cells, and a dominant-negative DACH1, DACH1-#DS, partially restored signaling in an ovarian cancer cell line resistant to TGF-B. These results suggest that altered expression of these genes is responsible for disrupted TGF-B signaling in ovarian cancer and they may be useful as new and novel therapeutic targets for ovarian cancer. (Cancer Res 2006; 66(17): 8404-12)

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Section: Discussionmentioning

confidence: 60%

Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-β Signaling in Ovarian Cancer

Sunde

Donninger²,

et al. 2006

Cancer Research

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“…EGF blocked Smad2/3 nuclear translocation in HaCat cells only when the TGFβ1 concentration was relatively low (Lo et al, 2001). Moreover, EGF had no effect on TGFβ1-mediated nuclear translocation of Smad2 in primary human cancer cells (Dunfield and Nachtigal, 2003). EGF did not block TGFβ1-mediated nuclear translocation of Smad2 in OKF6 cells at 1 hour, irrespective of the TGFβ1 treatment dose.…”

Section: Discussionmentioning

confidence: 96%

“…Also, hepatocyte growth factor (HGF) prevents, via ERK1/2, TGFβ1-mediated loss of E-cadherin in human proximal tubular epithelial cells (Yang et al, 2005). In addition, EGF blocks TGFβ1-mediated antiproliferative effects on primary human ovarian cells (Dunfield and Nachtigal, 2003). Overall, growth factor signaling in these particular examples abrogates the effect of TGFβ1 to maintain the cells in a more 'epithelial' state.…”

Section: Discussionmentioning

confidence: 99%

Differential growth factor regulation of N-cadherin expression and motility in normal and malignant oral epithelium

Diamond

Ottaviano

Joseph

et al. 2008

Journal of Cell Science

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promoter activity exclusively in oral keratinocytes but not in OSCC cells. The effect of EGF on TGFβ1-mediated Smad-driven promoter activity and N-cadherin expression was reversed when activation of ERK1/2 was blocked. Although EGF and TGFβ1 independently promoted migration of both oral keratinocytes and OSCC cells, EGF decreased TGFβ1-mediated migration of oral keratinocytes but enhanced migration of OSCC cells. Together, these data support a model wherein EGF signaling has an important negative regulatory role on TGFβ1-mediated N-cadherin expression and motility in normal oral keratinocytes, and in which loss of this regulatory mechanism accompanies malignant transformation of the oral epithelium.

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“…EGF also inhibits the TGFβ pathway through phosphorylation of Smad2/3 in the linker region, preventing nuclear translocation (Kretzschmar et al, 1999). EGF can also counteract the cytostatic effect of TGFβ by interfering with its ability to activate CDKI p15 INK4b (Dunfield and Nachtigal, 2003).…”

Section: Discussionmentioning

confidence: 99%

Retinal neurons regulate proliferation of postnatal progenitors and Müller glia in the rat retina via TGFβ signaling

2005

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Development 3016 glia and progenitors. The results of our experiments support a model in which TGFβ2, primarily derived from retinal neurons, inhibits proliferation of retinal progenitors and glia at the end of retinogenesis. Materials and methods Animals and injectionsAll animals used in this study were treated according to guidelines of the University of Washington IACUC. Long Evans rats were purchased from Charles River Laboratories. For P5.5 intraocular injections, animals were anesthetized by hypothermia, and their eyelids opened with iridectomy scissors. Proparacaine topical anesthetic was applied, followed by intraocular injection nasal to the cornea using a 30.5 G needle and Hamilton syringe. For P10 intraocular injections, P10/P11 animals were anesthetized with ketamine/xylazine and injected as described for P5.5 animals. Factors used for intraocular injection experiments include 40 nmoles SB-431542 in dimethylsulfoxide (Sigma) mTGFβRII-hFc (R&D Systems), mouse-anti-TGFβ blocking antibody (MAB1835, R&D Systems) and rhEGF (R&D Systems). BrdU injections were performed intraperitoneally using a sterile 30.5 G needle and 1 ml syringe. For the birthdating study, pups were weighed and given three injections of BrdU (50 mg/kg) over 9 hours on postnatal day 4, 6, 8, 10 or 12, sacrificed at P15 by CO 2 overanesthesia and processed for BrdU immunohistochemistry.

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Inhibition of the antiproliferative effect of TGFβ by EGF in primary human ovarian cancer cells

Cited by 29 publications

References 23 publications

Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-β Signaling in Ovarian Cancer

Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-β Signaling in Ovarian Cancer

Differential growth factor regulation of N-cadherin expression and motility in normal and malignant oral epithelium

Retinal neurons regulate proliferation of postnatal progenitors and Müller glia in the rat retina via TGFβ signaling

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