The type III TGF-β receptor suppresses breast cancer progression

Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 02/2007; 117(1):206-17. DOI: 10.1172/JCI29293
Source: PubMed


The TGF-beta signaling pathway has a complex role in regulating mammary carcinogenesis. Here we demonstrate that the type III TGF-beta receptor (TbetaRIII, or betaglycan), a ubiquitously expressed TGF-beta coreceptor, regulated breast cancer progression and metastasis. Most human breast cancers lost TbetaRIII expression, with loss of heterozygosity of the TGFBR3 gene locus correlating with decreased TbetaRIII expression. TbetaRIII expression decreased during breast cancer progression, and low TbetaRIII levels predicted decreased recurrence-free survival in breast cancer patients. Restoring TbetaRIII expression in breast cancer cells dramatically inhibited tumor invasiveness in vitro and tumor invasion, angiogenesis, and metastasis in vivo. TbetaRIII appeared to inhibit tumor invasion by undergoing ectodomain shedding and producing soluble TbetaRIII, which binds and sequesters TGF-beta to decrease TGF-beta signaling and reduce breast cancer cell invasion and tumor-induced angiogenesis. Our results indicate that loss of TbetaRIII through allelic imbalance is a frequent genetic event during human breast cancer development that increases metastatic potential.

Download full-text


Available from: Kellye Kirkbride, Jan 14, 2014
  • Source
    • "TGFbrIII expression is decreased in breast cancer cell lines and human breast cancer tissues (Dong et al., 2007, Lee et al., 2010; Sun & Chen, 1997). sTGFbrIII recapitulates the inhibitory effect of the membrane bound TGFbrIII on the invasion in breast cancer models (Dong et al., 2007). Proposed mechanism includes either sequestration of the TGFb superfamily ligands or signaling suppression (Gatza et al., 2014; Vilchis-Landeros et al., 2001), or their binding to the extracellular matrix and blockade of their ability to interact with TGFbrIII on the cell surface. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Type III transforming growth factor (TGFβ) receptor (TGFβrIII) modulates TGFβ superfamily signaling. Its tumor tissue expression is downregulated in human breast cancer. We determined (indirect ELISA) plasma levels of the soluble receptor (sTGFβrIII) in 47 women with breast cancer (AJCC stages 0-IIB) (cases) pre-surgery and over two months after the surgery, and in 36 healthy women (controls). Plasma sTBFβrIII was lower in cases than in the controls (age-adjusted difference -29.7 ng/mL, p < 0.001), and discriminated between disease and health (sensitivity and specificity 100% at 16.6 ng/mL). With adjustment for age, AJCC stage, lymph node involvement, HER2 and hormone receptor status, higher pre-surgery sTBFβrIII was associated with better progression-free survival (HR = 0.68, 95%CI 0.49-0.89, p = 0.004). An increasing trend in plasma sTBFβrIII was observed over 2 months after the surgery (0.6% increase/day, p < 0.001), consistently across the patient subsets. Data suggest a high potential of plasma sTBFβrIII as a novel diagnostic and prognostic biomarker in breast cancer.
    Growth factors (Chur, Switzerland) 07/2015; 33(3):1-10. DOI:10.3109/08977194.2015.1055740 · 3.39 Impact Factor
  • Source
    • "Previously, the loss of TβRIII expression was correlated with progression from a pre-invasive to an invasive state of breast cancer [18]. In addition, restoring expression of TβRIII in a breast cancer cell line led to a decrease of tumor invasiveness in vitro and tumor invasion and metastasis in vivo[18]. Other studies have demonstrated a frequent loss of TβRIII in human breast cancers [14-17,41]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction There is a major need to better understand the molecular basis of triple negative breast cancer (TNBC) in order to develop effective therapeutic strategies. Using gene expression data from 587 TNBC patients we previously identified six subtypes of the disease, among which a mesenchymal-stem like (MSL) subtype. The MSL subtype has significantly higher expression of the transforming growth factor beta (TGF-β) pathway-associated genes relative to other subtypes, including the TGF-β receptor type III (TβRIII). We hypothesize that TβRIII is tumor promoter in mesenchymal-stem like TNBC cells. Methods Representative MSL cell lines SUM159, MDA-MB-231 and MDA-MB-157 were used to study the roles of TβRIII in the MSL subtype. We stably expressed short hairpin RNAs specific to TβRIII (TβRIII-KD). These cells were then used for xenograft tumor studies in vivo; and migration, invasion, proliferation and three dimensional culture studies in vitro. Furthermore, we utilized human gene expression datasets to examine TβRIII expression patterns across all TNBC subtypes. Results TβRIII was the most differentially expressed TGF-β signaling gene in the MSL subtype. Silencing TβRIII expression in MSL cell lines significantly decreased cell motility and invasion. In addition, when TβRIII-KD cells were grown in a three dimensional (3D) culture system or nude mice, there was a loss of invasive protrusions and a significant decrease in xenograft tumor growth, respectively. In pursuit of the mechanistic underpinnings for the observed TβRIII-dependent phenotypes, we discovered that integrin-α2 was expressed at higher level in MSL cells after TβRIII-KD. Stable knockdown of integrin-α2 in TβRIII-KD MSL cells rescued the ability of the MSL cells to migrate and invade at the same level as MSL control cells. Conclusions We have found that TβRIII is required for migration and invasion in vitro and xenograft growth in vivo. We also show that TβRIII-KD elevates expression of integrin-α2, which is required for the reduced migration and invasion, as determined by siRNA knockdown studies of both TβRIII and integrin-α2. Overall, our results indicate a potential mechanism in which TβRIII modulates integrin-α2 expression to effect MSL cell migration, invasion, and tumorigenicity.
    Breast cancer research: BCR 07/2014; 16(4):R69. DOI:10.1186/bcr3684 · 5.49 Impact Factor
  • Source
    • "The human normal mammary epithelial cell lines, MCF10A and HMECs were cultured in F12/DMEM (1:1) + 5% horse serum, 10 μg/ml insulin, 0.5 μg/ml hydrocortisol, 20 ng/ml EGF, 100 ng/ml cholera toxin and DMEM + 10% FBS, 10 μg/ml insulin, respectively. MDA-MB-231, MCF-7, and 4T1 stable cell lines, representing a pool of stable clones, were derived as previously described and maintained in 250 μg/ml G418 [26] [30]. Viral Production and Infection. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily that are over-expressed in breast cancer, with context dependent effects on breast cancer pathogenesis. The type III TGF-β receptor (TβRIII) mediates BMP signaling. While TβRIII expression is lost during breast cancer progression, the role of TβRIII in regulating BMP signaling in normal mammary epithelium and breast cancer cells has not been examined. Restoring TβRIII expression in a 4T1 murine syngeneic model of breast cancer suppressed Smad1/5/8 phosphorylation and inhibited the expression of the BMP transcriptional targets, Id1 and Smad6, in vivo. Similarly, restoring TβRIII expression in human breast cancer cell lines or treatment with sTβRIII inhibited BMP-induced Smad1/5/8 phosphorylation and BMP-stimulated migration and invasion. In normal mammary epithelial cells, shRNA-mediated silencing of TβRIII, TβRIII over-expression, or treatment with sTβRIII inhibited BMP-mediated phosphorylation of Smad1/5/8 and BMP induced migration. Inhibition of TβRIII shedding through treatment with TAPI-2 or expression of a non-shedding TβRIII mutant rescued TβRIII mediated inhibition of BMP induced Smad1/5/8 phosphorylation and BMP induced migration and/or invasion in both in normal mammary epithelial cells and breast cancer cells. Conversely, expression of a TβRIII mutant, which exhibited increased shedding, significantly reduced BMP-mediated Smad1/5/8 phosphorylation, migration, and invasion. These data demonstrate that TβRIII regulates BMP-mediated signaling and biological effects, primarily through the ligand sequestration effects of sTβRIII in normal and cancerous mammary epithelial cells and suggest that the ratio of membrane bound versus sTβRIII plays an important role in mediating these effects.
    Neoplasia (New York, N.Y.) 06/2014; 16(6):489–500. DOI:10.1016/j.neo.2014.05.008 · 4.25 Impact Factor
Show more