Many advanced tumors produce excessive amounts of Transforming Growth Factor-β 
(TGF-β) which, in normal epithelial cells, is a potent growth inhibitor. 
However, in oncogenically activated cells, the homeostatic action of TGF-β is 
often diverted along alternative pathways. Hence, TGF-β signaling elicits 
protective or tumor suppressive effects during the early growth-sensitive stages 
of tumorigenesis. However, later in tumor development when carcinoma cells 
become refractory to TGF-β-mediated growth inhibition, the tumor cell responds 
by stimulating pathways with tumor progressing effects. At late stages of 
malignancy, tumor progression is driven by TGF-β overload. The tumor 
microenvironment is a target of TGF-β action that stimulates tumor progression 
via pro-tumorigenic effects on vascular, immune, and fibroblastic cells. Bone is 
one of the richest sources of TGF-β in the body and a common site for 
dissemination of breast cancer metastases. Osteoclastic degradation of bone 
matrix, which accompanies establishment and growth of metastases, triggers 
further release of bone-derived TGF-β. This leads to a vicious positive feedback 
of tumor progression, driven by ever increasing levels of TGF-β released from 
both the tumor and bone matrix. It is for this reason, that pharmaceutical 
companies have developed therapeutic agents that block TGF-β signaling. 
Nonetheless, the choice of drug design and dosing strategy can affect the 
efficacy of TGF-β therapeutics. This review will describe pre-clinical and 
clinical data of four major classes of TGF-β inhibitor, namely i) ligand traps, 
ii) antisense oligonucleotides, iii) receptor kinase inhibitors and iv) peptide 
aptamers. Long term dosing strategies with TGF-β inhibitors may be ill-advised, 
since this class of drug has potentially highly pleiotropic activity, and 
development of drug resistance might potentiate tumor progression. Current 
paradigms for the use of TGF-β inhibitors in oncology have therefore moved 
towards the use of combinatorial therapies and short term dosing, with 
considerable promise for the clinic.