The type III TGF-β receptor suppresses breast cancer progression

Abstract

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.

Gene expression meta-analysis identifies chromosomal regions and candidate genes involved in breast cancer metastasis

“…1b). Furthermore, TGFBR3 have recently been proposed as candidate gene on 1p [12], supported by the present data, although not fulfilling candidate gene selection criteria (supplementary Fig. 1b).…”

“…However, the promoter of Growth Arrest-and DNA Damage-inducible gene GADD45A is often methylated in breast cancer [32]. Another potential metastasis suppressor gene, TGFBR3, at 1p is proposed by Dong et al [12] who recently linked decreased expression of this gene with poor prognosis. This is supported by lowered expression of TGFBR3 in 6 of 8 datasets (supplementary Fig.…”

Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC

“…It is of note that 21 tumour-suppressor genes map within either the specific or the consistently altered regions. TIMP3 and PTEN have already been reported as tumour suppressors in thyroid tumours (Hu et al, 2006;Hou et al, 2007;Wang et al, 2007), while others are involved in a variety of different tumour types, for example, TGFBR3 and ANXA7 in prostate cancer (Torosyan et al, 2006;Dong et al, 2007), TNFSF15 and TUSC1 in lung cancer (Shan et al, 2004;Hou et al, 2005), SYK and Net1 in breast cancer (Repana et al, 2006;Huang et al, 2007), SLIT1, RSU1 and KLF6 in gliomas and glioblastosmas (Chunduru et al, 2002;Dickinson et al, 2004;Camacho-Vanegas et al, 2007), DBC1 in bladder cancer (Louhelainen et al, 2006), DEC1 in oesophageal squamous cell carcinomas (Yang et al, 2005), RB1 in retinoblastoma (Corson and Gallie, 2007) and LATS2 and DLEU7 in leukaemias (Hammarsund et al, 2004;Jimenez-Velasco et al, 2005). Some of these tumour suppressors have influence on the regulation of chromatin acetylation …”

Characterization of type III TGF‐β receptor expression in invasive breast carcinomas: a potential new marker and target for triple negative breast cancer

“…Loss of TBR3 expression has been reported in multiple cancers, with loss of expression correlating with progression and worse prognosis (Dong et al 2007;Gatza et al 2010;Mythreye and Blobe 2009;Hanks et al 2013;Gordon et al 2008). In breast cancer, TBR3 inhibits cell migration and invasion, supporting a tumor suppressor function (Dong et al 2007).…”