TGF-β switches from tumor suppressor to prometastatic factor in a model of breast cancer progression

Tang, Binwu; Vu, Mary; Booker, Timberly; Santner, Steven J.; Miller, Fred R.; Anver, Miriam R.; Wakefield, Lalage M.

doi:10.1172/jci200318899

Cited by 318 publications

(65 citation statements)

References 20 publications

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“…As BMP2-induced Smad2/3 phosphorylation preferentially occurs in embryonic or transformed cells, we sought to investigate whether dedifferentiation during cancer progression promotes this novel mode of BMP signaling. In a murine breast cancer cell line progression series (23,24), where the isogenic lines recapitulate cancer progression from normal epithelium, to locally invasive cancer, then to metastatic cancer, BMP2-induced Smad1/5/8 and Smad3 phosphorylation increased as the model progressed from recapitulation of benign to metastatic disease, whereas BMP2induced Smad2 phosphorylation oscillated ( Fig. 1E), suggesting that dedifferentiation during cancer progression promotes BMP2-induced Smad1/5/8 and Smad3 phosphorylation.…”

Section: Bmp2 Induces Smad2/3 Phosphorylation Preferentially In Embrymentioning

confidence: 98%

Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development

Holtzhausen¹,

Golzio

How

et al. 2013

FASEB j.

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The bone morphogenetic protein (BMP) signaling pathways have important roles in embryonic development and cellular homeostasis, with aberrant BMP signaling resulting in a broad spectrum of human disease. We report that BMPs unexpectedly signal through the canonical transforming growth factor β (TGF-β)-responsive Smad2 and Smad3. BMP-induced Smad2/3 signaling occurs preferentially in embryonic cells and transformed cells. BMPs signal to Smad2/3 by stimulating complex formation between the BMP-binding TGF-β superfamily receptors, activin receptor-like kinase (ALK)3/6, and the Smad2/3 phosphorylating receptors ALK5/7. BMP signaling through Smad2 mediates, in part, dorsoventral axis patterning in zebrafish embryos, whereas BMP signaling through Smad3 facilitates cancer cell invasion. Consistent with increased BMP-mediated Smad2/3 signaling during cancer progression, Smad1/5 and Smad 2/3 signaling converge in human cancer specimens. Thus, the signaling mechanisms used by BMPs and TGF-β superfamily receptors are broader than previously appreciated.

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Section: Bmp2 Induces Smad2/3 Phosphorylation Preferentially In Embrymentioning

confidence: 98%

Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development

Holtzhausen¹,

Golzio

How

et al. 2013

FASEB j.

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“…After transplantation, the size of each tumour mass developed was measured with a calliper twice a week and tumour volumes were calculated as previously described (Tang et al 2003). On day 22 after cell administration, all animals were killed under anaesthesia by intracardiac injection of pentobarbital (40 mg ⁄ kg) and tumours were removed from each animal.…”

Section: Tumourigenesismentioning

confidence: 99%

Tumourigenic effect of Schistosoma haematobium total antigen in mammalian cells

Botelho

Oliveira

Gomes

et al. 2009

Int J Experimental Path

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Schistosoma haematobium is endemic in several regions of Africa and has been shown to be associated with predominantly squamous cell bladder carcinoma. The mechanisms underlying the association between S. haematobium and bladder squamous cell carcinoma is largely unknown. All the reports so far, demonstrate exclusively an epidemiological evidence linking S. haematobium infection with squamous cell bladder carcinoma. We hypothesized that these parasite antigens might induce tumourigenesis. For this, we used normal mammalian cells of Chinese hamster ovary (CHO) and treated the cells in culture with S. haematobium total antigen (Sh). Our results showed increased proliferation in Sh-treated cells in comparison with the controls. The CHO cells exposed to Sh were inoculated subcutaneously into male nude mice and formed sarcomas (n = 5/5). The cells from the sarcomas expressed vimentin filaments and were negative to cytokeratin. Our results demonstrate for the first time that S. haematobium antigens induce tumour development in nude mice.

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“…In vitro studies have shown that TGF-βRII is required for TGF-β 1 -mediated tumor invasion (8,9). Decreased breast cancer metastasis was seen in a model expressing a dominant negative TGF-βRII (∆βRII) transgene in human breast-derived cell lines (10). In contrast, increased skin cancer metastasis and prostate cancer metastasis were observed in the respective ∆βRII-transgenic models (11,12).…”

Section: Introductionmentioning

confidence: 99%

Distinct mechanisms of TGF- 1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis

Han¹

2005

Journal of Clinical Investigation

210

186

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In the present study, we demonstrated that human skin cancers frequently overexpress TGF-β 1 but exhibit decreased expression of the TGF-β type II receptor (TGF-βRII). To understand how this combination affects cancer prognosis, we generated a transgenic mouse model that allowed inducible expression of TGF-β 1 in keratinocytes expressing a dominant negative TGF-βRII (∆βRII) in the epidermis. Without ∆βRII expression, TGF-β 1 transgene induction in late-stage, chemically induced papillomas failed to inhibit tumor growth but increased metastasis and epithelial-to-mesenchymal transition (EMT), i.e., formation of spindle cell carcinomas. Interestingly, ∆βRII expression abrogated TGF-β 1 -mediated EMT and was accompanied by restoration of membrane-associated E-cadherin/catenin complex in TGF-β 1 /∆βRII compound tumors. Furthermore, expression of molecules thought to mediate TGF-β 1 -induced EMT was attenuated in TGF-β 1 /∆βRII-transgenic tumors. However, TGF-β 1 /∆βRII-transgenic tumors progressed to metastasis without losing expression of the membrane-associated E-cadherin/catenin complex and at a rate higher than those observed in nontransgenic, TGF-β 1 -transgenic, or ∆βRII-transgenic mice. Abrogation of Smad activation by ∆βRII correlated with the blockade of EMT. However, ∆βRII did not alter TGF-β 1 -mediated expression of RhoA/Rac and MAPK, which contributed to increased metastasis. Our study provides evidence that TGF-β 1 induces EMT and invasion via distinct mechanisms. TGF-β 1 -mediated EMT requires functional TGF-βRII, whereas TGF-β 1 -mediated tumor invasion cooperates with reduced TGF-βRII signaling in tumor epithelia.

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TGF-β switches from tumor suppressor to prometastatic factor in a model of breast cancer progression

Cited by 318 publications

References 20 publications

Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development

Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development

Tumourigenic effect of Schistosoma haematobium total antigen in mammalian cells

Distinct mechanisms of TGF- 1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis

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