Gain or loss of TGF-β signaling in mammary carcinoma cells can promote metastasis

Bierie, Brian; Moses, Harold L.

doi:10.4161/cc.8.20.9727

Cited by 56 publications

(38 citation statements)

References 78 publications

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“…During the early stages of carcinogenesis, TGF-β1 exhibits a predominantly inhibitory effect on growth, and serves as a tumor suppressor. However, with the development of malignancy, TGF-β1 promotes tumor cell invasion and metastasis (8,9). Previous studies have demonstrated that high expression levels of TGF-β1 have a close association with gastric cancer (10), lung cancer (11), colon cancer (10,12) and other malignant tumors.…”

Section: Discussionmentioning

confidence: 99%

Association between transforming growth factor-β1 expression and the clinical features of triple negative breast cancer

Ding

Cui

et al. 2016

Oncology Letters

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Abstract. The aim of the present study was to investigate the association between the expression levels of transforming growth factor-β1 (TGF-β1) and the clinical pathological characteristics and prognosis of triple negative breast cancer (TNBC) through study of TNBC patient tissue samples. The biological effects of TGF-β1 on TNBC cells and the potential signal transduction pathway are additoinally investigated. Immunohistochemistry was utilized to investigate expression changes of the positive rate of TGF-β1 in the TNBC, compared with the non-TNBC group, to explain the association between TGF-β1 and clinical pathological characteristics and prognosis. MDA-MB-231 cells were treated with TGF-β1 and subsequently the invasion and migration abilities, and the expression of proteins in certain signaling pathways were assessed before and after the treatment. Positive expression of TGF-β1 was observed in 52.5% of TNBC tissue samples, which was higher than that observed in non-TNBC group (27.5%). High levels of TGF-β1 expression were not significantly associated age, menopausal status, family history of cancer or tumor size; however, tumor histological grade and axillary lymph node metastasis were significantly associated (P<0.05). In addition, when the TGF-β1 expression levels are higher, the 5-year disease-free survival rate is lower. TGF-β1 expression promoted the invasion and migration of MDA-MB-231 cells, and the expression of Smad2 protein and P38 protein was increased, indicating that Smad2 protein and the P38 signaling pathway may serve an important role in TNBC.

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Section: Discussionmentioning

confidence: 99%

Association between transforming growth factor-β1 expression and the clinical features of triple negative breast cancer

Ding

Cui

et al. 2016

Oncology Letters

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“…Although Tgfbr2 exon2 deletion is not a model for kinase-mutant receptors in Loeys-Dietz syndrome, the similar medial degeneration in both situations suggests that either deficient or excess TGF-β signaling may disrupt SMC homeostasis. There are several examples of context-dependent roles of TGF-β in disease pathogenesis, such as either gain or loss of signaling in carcinoma cells promoting metastasis (49) or resulting in heterotaxy and congenital heart disease (50). In support of a protective role in arterial disease, TGF-β prevents aortic dilatation in various murine models of immunomediated vascular remodeling (51-54) and protects against immunologic injury of SMCs in experimental human systems of arteriosclerosis (55,56).…”

Section: Methodsmentioning

confidence: 99%

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

et al. 2014

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TGF-β is essential for vascular development; however, excess TGF-β signaling promotes thoracic aortic aneurysm and dissection in multiple disorders, including Marfan syndrome. Since the pathology of TGF-β overactivity manifests primarily within the arterial media, it is widely assumed that suppression of TGF-β signaling in vascular smooth muscle cells will ameliorate aortic disease. We tested this hypothesis by conditional inactivation of Tgfbr2, which encodes the TGF-β type II receptor, in smooth muscle cells of postweanling mice. Surprisingly, the thoracic aorta rapidly thickened, dilated, and dissected in these animals. Tgfbr2 disruption predictably decreased canonical Smad signaling, but unexpectedly increased MAPK signaling. Type II receptor-independent effects of TGF-β and pathological responses by nonrecombined smooth muscle cells were excluded by serologic neutralization. Aortic disease was caused by a perturbed contractile apparatus in medial cells and growth factor production by adventitial cells, both of which resulted in maladaptive paracrine interactions between the vessel wall compartments. Treatment with rapamycin restored a quiescent smooth muscle phenotype and prevented dissection. Tgfbr2 disruption in smooth muscle cells also accelerated aneurysm growth in a murine model of Marfan syndrome. Our data indicate that basal TGF-β signaling in smooth muscle promotes postnatal aortic wall homeostasis and impedes disease progression.

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“…Many factors regulate metastatic spread of breast cancer cells [1], both those that are intrinsic to tumor cells [2][3][4], and host-associated elements [5][6][7]. In mouse models, expression of chemokines or chemokine receptors [8][9][10] regulates metastatic spread, possibly by recruiting inflammatory-type cells to the local tumor environment, which produce angiogenic factors and matrix-degrading enzymes [7,11].…”

Section: Introductionmentioning

confidence: 99%

Role of CD200 expression in regulation of metastasis of EMT6 tumor cells in mice

Gorczynski

Clark

Erin

et al. 2010

Breast Cancer Res Treat

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Previous studies have confirmed that levels of CD200 expression on the cells of the transplantable EMT6 mouse breast cancer line are increased markedly during growth in immunocompetent mice, unlike the persistent low levels of expression observed in NOD-SCID.IL-2(γr-/-) mice or mice with generalized over-expression of a CD200 transgene (CD200(tg) mice). Faster tumor growth occurs in both of these latter mice, with decreased evidence for a host immune reaction in lymph nodes draining the tumor (DLN). We now report evidence for a role for CD200 expression (by the host and/or tumor cells) in increased seeding of tumor cells to DLN in immunocompromised (CD200(tg) or NOD-SCID.IL-2(γr-/-)) vs immunocompetent mice, by limiting dilution cloning of tumor cells from DLN (vs contralateral lymph nodes, CLN), using control and GFP-tagged EMT6 cells. Neutralization of expressed CD200 by anti-CD200mAbs decreased the tumor metastasis at the same time as increasing detection of cytotoxic anti-tumor immune cells in DLN. Infusion of either anti-CD4 to deplete T-effector cells, or anti-TGFβ antibody, increased metastasis to DLN, as did indeed the infusion of EMT6 cells selected for the loss of TGFβRII expression. It is concluded that the increased CD200 expression by breast cancer cells (and/or host tissue) may be an important variable involved in determining the risk of metastasis.

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Gain or loss of TGF-β signaling in mammary carcinoma cells can promote metastasis

Cited by 56 publications

References 78 publications

Association between transforming growth factor-β1 expression and the clinical features of triple negative breast cancer

Association between transforming growth factor-β1 expression and the clinical features of triple negative breast cancer

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

Role of CD200 expression in regulation of metastasis of EMT6 tumor cells in mice

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