Abstract
BackgroundThe transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) signaling pathways are both constitutively activated in triple-negative breast cancer (TNBC). We are interested in isolating the naturally-derived small-molecule inhibitor that could simultaneously targeting TGFβ/BMP pathways and further studying its anti-proliferative/−metastatic effects as well as the underlying mechanisms in multiple tumor models.MethodsMultiple in vitro cell-based assays are used to examine the compound’s inhibitory efficacy on TNBC cell growth, stemness, epithelial-mesenchymal transition (EMT), invasion and migration by targeting TGFβ/BMP signaling pathways. Transgenic breast cancer mouse model (MMTV-PyMT), subcutaneous xenograft and bone metastasis models are used to examine ZL170’s effects on TNBC growth and metastasis potentials in vivo.ResultsZL170 dose-dependently inhibits cell proliferation, EMT, stemness, invasion and migration in vitro via specifically targeting canonical TGFβ/BMP-SMADs pathways in TNBC cells. The compound significantly hinders osteolytic bone metastasis and xenograft tumor growth without inflicting toxicity on vital organs of tumor-bearing nude mice. ZL170 strongly inhibits primary tumor growth and lung metastases in MMTV-PyMT transgenic mice. ZL170-treated tumors exhibit impaired TGFβ/BMP signaling pathways in both epithelial and stromal compartments, thereby creating a suppressive tumor microenvironment characterized by reduced extracellular matrix deposition and decreased infiltration of stromal cells.ConclusionsZL170 inhibits tumor EMT, stemness and metastasis and could be further developed as a potent anti-metastatic agent used in combination with cytotoxic drugs for treatment of TNBC and other advanced metastatic cancers.
Highlights
The transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) signaling pathways are both constitutively activated in triple-negative breast cancer (TNBC)
ZL170 targets the TGFβ and BMP signaling pathways in TNBC cells We first sought to determine whether ZL170 could affect cell migration and invasion in a variety of basal, TNBC cell lines
ZL170-treated cells demonstrated reduced expression of extracellular matrix (ECM) remodeling genes (MMP1, MMP2, MMP9, MMP13, MMP14), bone metastasis-promoting genes (ADAM19, PMEPA1, THBS1, IL11), cell growth-stimulating genes (ID1 and ID3), epithelial-mesenchymal transition (EMT)-Transfer factor (TF) (Snail and Slug) and cancer stem cell (CSC)-TFs (SOX2 and Nanog) but increased expression of tumor suppressors (p15 and p21), all of which are recognized as direct TGFβ and BMP targets [2, 7, 16, 17] and were further confirmed by reverse transcription-quantitative PCR (RT-qPCR) (Fig. 1c and e)
Summary
The transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) signaling pathways are both constitutively activated in triple-negative breast cancer (TNBC). The transforming growth factor β (TGFβ) superfamily of cytokines, which comprises three TGFβ isoforms (TGFβ1, TGFβ2 and TGFβ3), bone morphogenetic proteins (BMPs; BMP1 ~ BMP7), nodals, activins, inhibins and others, is evolutionarily conserved and actively involved in many cellular processes including cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, angiogenesis and immune suppression [1,2,3,4]. TGFβ and BMPs transduce their signals through two highly conserved single transmembrane serine/threonine kinase receptors, termed type II receptors (TGFBR2 for TGFβ and BMPR2 for BMPs) and type I receptors (TGFBR1 (i.e. ALK5) for TGFβ and BMPR1A/1B (i.e. ALK3/6) for BMPs). TGFβ and BMPs inhibit cell growth and act as tumor suppressors, while in later stages, they promote cell proliferation, EMT, stemness, invasion and metastasis [2, 6, 7]
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