Abstract
BackgroundTransforming Growth Factor β (TGF-β) plays an important role in tumor invasion and metastasis. We set out to investigate the possible clinical utility of TGF-β antagonists in a human metastatic basal-like breast cancer model. We examined the effects of two types of the TGF-β pathway antagonists (1D11, a mouse monoclonal pan-TGF-β neutralizing antibody and LY2109761, a chemical inhibitor of TGF-β type I and II receptor kinases) on sublines of basal cell-like MDA-MB-231 human breast carcinoma cells that preferentially metastasize to lungs (4175TR, 4173) or bones (SCP2TR, SCP25TR, 2860TR, 3847TR).ResultsBoth 1D11 and LY2109761 effectively blocked TGF-β-induced phosphorylation of receptor-associated Smads in all MDA-MB-231 subclones in vitro. Moreover, both antagonists inhibited TGF-β stimulated in vitro migration and invasiveness of MDA-MB-231 subclones, indicating that these processes are partly driven by TGF-β. In addition, both antagonists significantly reduced the metastatic burden to either lungs or bones in vivo, seemingly independently of intrinsic differences between the individual tumor cell clones. Besides inhibiting metastasis in a tumor cell autonomous manner, the TGF-β antagonists inhibited angiogenesis associated with lung metastases and osteoclast number and activity associated with lytic bone metastases. In aggregate, these studies support the notion that TGF-β plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-β signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-β pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer.ConclusionsIn aggregate, these studies support the notion that TGF-β plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-β signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-β pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer.
Highlights
Transforming Growth Factor β (TGF-β) plays an important role in tumor invasion and metastasis
Several investigators have demonstrated that genetic inactivation of the TGF-β signaling pathway reduces the ability of human basal-like breast cancer cells to metastasize to bones or lungs [23,24,25,26,27,29]
The first question we addressed is whether treatment with pharmacological TGF-β antagonists can reproduce the effects of genetically inactivating the tumor cell autonomous TGF-β signaling pathway in vitro and in vivo
Summary
Transforming Growth Factor β (TGF-β) plays an important role in tumor invasion and metastasis. A significantly greater fraction of invasive carcinomas express immunodetectable TGF-β than in situ carcinomas [19,20] Besides these correlative studies, genetic manipulation of the intrinsic TGF-β signaling pathway in mammary cancer cells has provided direct evidence for its importance in driving the metastatic process (Reviewed in [21]). Interference with Smad2/3 signaling strongly suppressed experimental lung metastases of aggressive MCF10Ca breast carcinoma cells [29] In aggregate, these studies indicate that, even though human breast carcinoma cells are typically refractory to TGF-β-mediated growth suppression, the remaining intrinsic TGF-β signaling contributes to the formation of macrometastases in several different secondary sites, including bone and lungs [23,24,25]. A number of key questions will need to be answered before embarking on clinical trials of TGF-β pathway antagonists in breast cancer
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