Targeting the Transforming Growth Factor-β pathway inhibits human basal-like breast cancer metastasis

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.

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

“…39 MDA-MB-231 cells belong to those tumor cells, which are resistant to the growth inhibition of TGF-b1, although they are responsive with respect to TGF-b1-induced gene expression. 40 This supports the role of autocrine TGF-b1 in tumor progression in this cell type. SPP1 is a TGF-b1 target gene.…”

YKL-40/CHI3L1 drives inflammation on the road of tumor progression

“…TAMs contribute to tumor growth and metastasis by secreting MMPs that promote extracellular matrix remodeling; angiogenic factors that increase blood vessel formation; and cytokines, chemokines, and growth factors that enhance tumor growth [18,19]. Specifically, TAMs have been reported to produce VEGF, epidermal growth factor, basic fibroblast growth factor, platelet-derived growth factor, IL-6, MCP-1, CXCL18, CXCL12, and YKL-40/CHI3L1 [16,[20][21][22][23][24][25]. YKL-40/CHI3L1 induces the expression of MCP-1/CCL2 and IL-8/CXCL2, which are chemoattractants for monocytes/ macrophages and neutrophils [16].…”

An engineered transforming growth factor β (TGF-β) monomer that functions as a dominant negative to block TGF-β signaling

“…TGF-␤'s disease promoting activities, together with animal studies that have demonstrated beneficial effects of inhibiting TGF-␤ in models of cancer and fibrosis (15)(16)(17)(18)(19)(20)(21)(22), have made them important targets for the development of inhibitors. However, despite clinical trials ongoing for nearly 2 decades using receptor kinase inhibitors, neutralizing antibodies, and other approaches, no TGF-␤ inhibitors have been approved for clinical use in humans (23,24).…”