Loss of expression of transforming growth factor beta type II receptor correlates with high tumour grade in human breast in‐situ and invasive carcinomas

Gobbi, Helenice; Arteaga, CL; Ra, Jensen; Jf, Simpson; Wd, Dupont; Sj, Olson; Pa, Schuyler; Wd, Plummer; Page, D. L.

doi:10.1046/j.1365-2559.2000.00841.x

Cited by 107 publications

(86 citation statements)

References 56 publications

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“…These findings suggest that cancer cells could result in escape from autocrine growth inhibitory effect of TGF-b due to the loss of TbRII. A correlation between diminished expression of TbRII in breast cancer cells and enhanced in vivo malignant behaviour has been observed in studies based on patient specimens and an established cell line (Gobbi et al, 2000), suggesting that attenuation of the growth inhibitory TGF-b autocrine loop in breast cancers worsens clinical outcome. However, little is known about the TbRII status in lung cancer and whether restoring TGF-b signalling by the introduction of functional TGF-b type II receptor alters tumorigenicity in TGF-b unresponsive lung cancer cell lines that do not express the type II receptor.…”

mentioning

confidence: 84%

Restoration of TGF-β signalling reduces tumorigenicity in human lung cancer cells

et al. 2005

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Members of the transforming growth factor-b (TGF-b) family regulate a wide range of biological processes including cell proliferation, migration, differentiation, apoptosis, and extracellular matrix deposition. Resistance to TGF-b-mediated tumour suppressor function in human lung cancer may occur through the loss of type II receptor (TbRII) expression. In this study, we investigated the expression pattern of TbRII in human lung cancer tissues by RT -PCR and Western blot analyses. We observed downregulation of TbRII in 30 out of 46 NSCLC samples (65%) by semiquantitative RT -PCR. Western blot analyses with tumour lysates showed reduced expression of TbRII in 77% cases. We also determined the effect of TbRII expression in lung adenocarcinoma cell line (VMRC-LCD) that is not responsive to TGF-b due to lack of TbRII expression. Stable expression of TbRII in these cells restored TGF-b-mediated effects including Smad2/3 and Smad4 complex formation, TGF-b-responsive reporter gene activation, inhibition of cell proliferation and increased apoptosis. Clones expressing TbRII showed reduced colony formation in soft-agarose assay and significantly reduced tumorigenicity in athymic nude mice. Therefore, these results suggest that reestablishment of TGF-b signalling in TbRII null cells by stable expression of TbRII can reverse malignant behaviour of cells and loss of TbRII expression may be involved in lung tumour progression.

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confidence: 84%

Restoration of TGF-β signalling reduces tumorigenicity in human lung cancer cells

et al. 2005

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“…TGF-β1 is the most abundant form of TGF-β and regulates cellular processes by binding to TGFBR2, which then activates TGFBR1 through phosphorylation (3). Inactivation of the TGF-β signaling pathway may lead to acquisition of resistance to the anti-mitogenic effects of TGF-β and contribute to tumor development and progression (4,5). Therefore, defective expression or inactivation of TGF-β1 and its receptors, such as TGFBR2, may play a significant role in carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

A functional polymorphism of TGFBR2 is associated with risk of breast cancer with ER+, PR+, ER+PR+ and HER2− expression in women

Zhang¹,

Guo²,

Cheng³

et al. 2011

Oncology Letters

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Abstract.Little is known about the correlation between TGFBR2 G-875A and breast cancer risk. Moreover, the associations of the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) in breast cancer tissues with the TGFB1 C-509T, T+29C and TGFBR2 G-875A polymorphisms remain to be determined. In this study, we genotyped for TGFB1 C-509T, T+29C and TGFBR2 G-875A in fresh surgically resected tissues (n=82) and archived paraffin-embedded specimens (n=88) from 170 patients with breast cancer, as well as peripheral blood samples from 178 cancer-free female individuals. Evaluation of ER, PR and HER2 expression was performed using immunohistochemical staining. Logistic regression analysis was carried out to determine the risk of breast cancer by calculating the odds ratios (ORs) and their 95% confidence intervals (CIs). As a result, no difference was observed in the TGFB1 C-509T, T+29C genotype and allele frequencies between patients and controls. However, the frequency of the TGFBR2 -875A allele was marginally higher in cancer-free female individuals than that of women with breast cancer (24.2 vs. 17.9%, P=0.05). Notably, when stratification was performed by ER, PR and HER2 expression, the TGFBR2 -875A allele was found to correlate significantly to a decreased risk of breast cancer with ER + (OR=0.57, 95% CI 0.

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“…In accordance with these ®ndings, Lowsky and coworkers could recently show that lymphomas of MSH2 knockout mice (MSH27/7) ± mice lacking the mismatch repair system ± frequently exhibit mutations in the type II TGF-b receptor (Lowsky et al, 2000). Apart from mutations of the type II TGF-b receptor, downregulation or lack of expression of this receptor might be another means of escape from TGF-b mediated growth control as shown for prostate cancer (Cardillo et al, 2000), breast cancer (Gobbi et al, 2000) and also for hepatocellular carcinoma (Bedossa et al, 1995;Kiss et al, 1997;Factor et al, 1998). Some manifest hepatocellular carcinomas showed a marked reduction or loss of expression of TbRII (Bedossa et al, 1995;Kiss et al, 1997;Factor et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Hepatocellular expression of a dominant-negative mutant TGF-β type II receptor accelerates chemically induced hepatocarcinogenesis

Kanzler¹,

Meyer²,

Lohse³

et al. 2001

Oncogene

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The potent growth-inhibitory activity of cytokines of the transforming growth factor-b (TGF-b) superfamily and their widespread expression in epithelia suggest that they may play an important role in the maintenance of epithelial homeostasis. To analyse TGF-b mediated tumor suppressor activity in the liver, we generated transgenic mice overexpressing a dominant negative type II TGF-b receptor in hepatocytes under control of the regulatory elements of the human C-reactive protein gene promoter. Transgenic animals exhibited constitutive and liverspeci®c transgene expression. The functional inactivation of the TGF-b signaling pathway in transgenic hepatocytes was shown by reduced TGF-b induced inhibition of DNA synthesis in primary hepatocyte cultures. Liver morphology and spontaneous tumorigenesis were unchanged in transgenic mice suggesting that interruption of the signaling of all three isoforms of TGF-b in hepatocytes does not disturb tissue homeostasis in the liver under physiological conditions. However, following initiation with the carcinogen diethylnitrosamine and tumor-promotion with phenobarbital transgenic mice exhibited a moderate albeit signi®cant increase in the incidence, size and multiplicity of both preneoplastic tissue lesions in the liver and of hepatocellular carcinomas. These results give in vivo evidence for a tumor suppressor activity of the endogeneous TGF-b system in the liver during chemical hepatocarcinogenesis. Oncogene (2001) 20, 5015 ± 5024.

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Loss of expression of transforming growth factor beta type II receptor correlates with high tumour grade in human breast in‐situ and invasive carcinomas

Abstract: These data indicate that decreased expression of TGFbeta-RII may contribute to breast cancer progression and is related to a more aggressive phenotype in both in-situ and invasive carcinomas.

Cited by 107 publications

References 56 publications

Restoration of TGF-β signalling reduces tumorigenicity in human lung cancer cells

Restoration of TGF-β signalling reduces tumorigenicity in human lung cancer cells

A functional polymorphism of TGFBR2 is associated with risk of breast cancer with ER+, PR+, ER+PR+ and HER2− expression in women

Hepatocellular expression of a dominant-negative mutant TGF-β type II receptor accelerates chemically induced hepatocarcinogenesis

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