Abstract
BackgroundFollistatin (FST) is an intrinsic inhibitor of activin, a member of the transforming growth factor-β superfamily of ligands. The prognostic value of FST and its family members, the follistatin-like (FSTL) proteins, have been studied in various cancers. However, these studies, as well as limited functional analyses of the FSTL proteins, have yielded conflicting results on the role of these proteins in disease progression. Furthermore, very few have been focused on FST itself. We assessed whether FST may be a suppressor of tumorigenesis and/or metastatic progression in breast cancer.MethodsUsing publicly available gene expression data, we examined the expression patterns of FST and INHBA, a subunit of activin, in normal and cancerous breast tissue and the prognostic value of FST in breast cancer metastases, recurrence-free survival, and overall survival. The functional effects of activin and FST on in vitro proliferation, migration, and invasion of breast cancer cells were also examined. FST overexpression in an autochthonous mouse model of breast cancer was then used to assess the in vivo impact of FST on metastatic progression.ResultsExamination of multiple breast cancer datasets revealed that FST expression is reduced in breast cancers compared with normal tissue and that low FST expression predicts increased metastasis and reduced overall survival. FST expression was also reduced in a mouse model of HER2/Neu-induced metastatic breast cancer. We found that FST blocks activin-induced breast epithelial cell migration in vitro, suggesting that its loss may promote breast cancer aggressiveness. To directly determine if FST restoration could inhibit metastatic progression, we transgenically expressed FST in the HER2/Neu model. Although FST had no impact on tumor initiation or growth, it completely blocked the formation of lung metastases.ConclusionsThese data indicate that FST is a bona fide metastasis suppressor in this mouse model and support future efforts to develop an FST mimetic to suppress metastatic progression.
Highlights
Follistatin (FST) is an intrinsic inhibitor of activin, a member of the transforming growth factor-β superfamily of ligands
By examining intrinsic changes that occur in a mouse model of HER2/Neu receptor [26] to generate single (Neu)-induced metastatic breast cancer, we previously reported that activin receptor-like kinase 4 and phosphorylated Smad2 are present within tumors, whereas tumors had lost expression of transforming growth factor β-receptor 1 (TGF-βR1) [21]
To determine if activin may have a role in breast cancer, we examined several publicly available gene expression datasets and found that the gene encoding the activin A subunit, INHBA, is upregulated in the majority of breast tumors compared with normal breast tissue in three independent datasets (Fig. 1a and Additional file 2: Figure S1a)
Summary
Follistatin (FST) is an intrinsic inhibitor of activin, a member of the transforming growth factor-β superfamily of ligands. There are relatively few proteins that have been identified as true metastasis suppressors (i.e., factors that block metastatic progression without impacting primary tumor growth). Such suppressors may function to inhibit intrinsic enhancers of metastatic progression. Activin can increase the in vitro migratory and invasive capacity of several epithelial cancer cell lines [2, 3] These results suggest that activin may promote metastatic progression of cancer, but this supposition has not been fully assessed. Interconversion of differentiated breast cancer cells into stem cells requires activin/nodal signaling [5], and one of the most predictive genes within a core metastasis-associated expression signature of multiple cancers is INHBA, which encodes an activin and inhibin subunit [6]
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