Dataset Information

Chemotherapeutic Targeting of the Transforming Growth Factor-? Pathway in Breast Cancers.

ABSTRACT: Transforming growth factor (TGF-?) is a multifunctional cytokine that plays essential roles in regulating mammary gland development, morphogenesis, differentiation, and involution. TGF-? also regulates mammary gland homeostasis and prevents its transformation by prohibiting dysregulated cell cycle progression, and by inducing apoptosis; it also creates cell microenvironments that readily inhibit cell migration, invasion, and metastasis. Interestingly, while early-stage mammary tumors remain sensitive to the tumor suppressing activities of TGF-?, late-stage breast cancers become insensitive to the anticancer functions of this cytokine and instead rely upon TGF-? to drive disease and metastatic progression. This switch in TGF-? function is known as the "TGF-? Paradox" and represents the rationale for developing chemotherapies to inactivate the TGF-? pathway and its oncogenic functions in late-stage breast cancers. Here we outline the molecular mechanisms that manifest the "TGF-? Paradox" and discuss the challenges associated with the development and use of anti-TGF-? agents to treat breast cancer patients.

SUBMITTER: Lee YH

PROVIDER: S-EPMC4403665 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Chemotherapeutic Targeting of the Transforming Growth Factor-β Pathway in Breast Cancers.

Lee Yong-Hun YH Schiemann William P WP

Breast cancer management 20140101 1

Transforming growth factor (TGF-β) is a multifunctional cytokine that plays essential roles in regulating mammary gland development, morphogenesis, differentiation, and involution. TGF-β also regulates mammary gland homeostasis and prevents its transformation by prohibiting dysregulated cell cycle progression, and by inducing apoptosis; it also creates cell microenvironments that readily inhibit cell migration, invasion, and metastasis. Interestingly, while early-stage mammary tumors remain sens ...[more]

PMID: 25904986

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Project description:Osteosarcoma is a rare type of bone cancer, and half of the cases affect children and adolescents younger than 20 years of age. Despite intensive efforts to improve both chemotherapeutics and surgical management, the clinical outcome for metastatic osteosarcoma remains poor. Transforming growth factor β (TGF-β) is one of the most abundant growth factors in bones. The TGF-β signaling pathway has complex and contradictory roles in the pathogenesis of human cancers. TGF-β is primarily a tumor suppressor that inhibits proliferation and induces apoptosis of premalignant epithelial cells. In the later stages of cancer progression, however, TGF-β functions as a metastasis promoter by promoting tumor growth, inducing epithelial-mesenchymal transition (EMT), blocking antitumor immune responses, increasing tumor-associated fibrosis, and enhancing angiogenesis. In contrast with the dual effects of TGF-β on carcinoma (epithelial origin) progression, TGF-β seems to mainly have a pro-tumoral effect on sarcomas including osteosarcoma (mesenchymal origin). Many drugs that target TGF-β signaling have been developed: neutralizing antibodies that prevent TGF-β binding to receptor complexes; ligand trap employing recombinant Fc-fusion proteins containing the soluble ectodomain of either type II (TβRII) or the type III receptor ((TβRIII), preventing TGF-β from binding to its receptors; antisense nucleotides that reduce TGF-β expression at the transcriptional/translational level; small molecule inhibitors of serine/threonine kinases of the type I receptor (TβRI) preventing downstream signaling; and vaccines that contain cell lines transfected with TβRII antisense genes, or target furin convertase, resulting in reduced TGF-β signaling. TGF-β antagonists have been shown to have effects on osteosarcoma in vitro and in vivo. One of the small molecule TβRI inhibitors, Vactosertib, is currently undergoing a phase 1/2 clinical trial to evaluate its effect on osteosarcoma. Several phase 1/2/3 clinical trials have shown TGF-β antagonists are safe and well tolerated. For instance, Luspatercept, a TGF-β ligand trap, has been approved by the FDA for the treatment of anemia associated with myeloid dysplastic syndrome (MDS) with ring sideroblasts/mutated SF3B1 with acceptable safety. Clinical trials evaluating the long-term safety of Luspatercept are in process.

Dataset Information

Chemotherapeutic Targeting of the Transforming Growth Factor-? Pathway in Breast Cancers.

Publications

Chemotherapeutic Targeting of the Transforming Growth Factor-β Pathway in Breast Cancers.

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