The type III TGF-β receptor suppresses breast cancer progression

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