Activin A Signaling Regulates IL13Rα2 Expression to Promote Breast Cancer Metastasis

Abstract

Metastatic dissemination of cancer cells to distal organs is the major cause of death for patients suffering from the aggressive basal-like breast cancer (BLBC) subtype. Recently, we have shown that interleukin 13 receptor alpha 2 (IL13Rα2) is a critical gene that is overexpressed in a subset of BLBC primary tumors associated with poor distant metastasis-free survival (DMFS) and can promote extravasation and metastasis of breast cancer cells to the lungs. However, the upstream signaling mechanisms that promote aberrant IL13Rα2 expression during tumor progression remain unknown. Driven by our previously published gene expression microarray data derived from a well-characterized cell line model for BLBC progression, we show that both Inhibin βA (INHBA) and IL13Rα2 genes exhibit similarly higher expression levels in metastatic compared to non-metastatic cells and that overexpression of both genes predicts worse metastasis-free survival of patients with high grade tumors. Activin A, a member of the TGFβ superfamily comprising two INHBA subunits, has been shown to play context-depended roles in cancer progression. Here, we demonstrate that INHBA depletion downregulates IL13Rα2 expression in metastatic breast cancer cells, whereas treatment with Activin A in non-metastatic cells increases its expression levels. We also find that Activin A predominantly induces Smad2 phosphorylation and to a lesser extent activates Smad3 and Akt. Interestingly, we also show that Activin A-mediated upregulation of IL13Rα2 is Smad2-dependent since knocking down Smad2 or using the ALK4/ALK5 inhibitors EW-7197 and SB-505124 abolishes this effect. Most importantly, our data indicate that knocking down INHBA levels in breast cancer cells delays primary tumor growth, suppresses migration in vitro and inhibits the formation of lung metastases in vivo. Conclusively, our findings presented here suggest that the development of therapeutic interventions employing small molecule inhibitors against Activin receptors or neutralizing antibodies targeting Activin A ligand, could serve as alternative approaches against breast tumors overexpressing INHBA and/or IL13Rα2.

Activin A: an emerging target for improving cancer treatment?

“…Loss of E-cadherin represents a hallmark of EMT, which is frequently associated with increased cell invasion, and also contributes to activin A-induced invasion in breast cancer cells [54]. In a separate study, knockdown of activin A in breast cancer cells was shown to suppress migration in vitro and inhibit lung metastasis in vivo by inducing interleukin 13 receptor alpha 2 (IL13Rα2) overexpression [51].…”

“…While the response of normal and tumor cells to activin A with respect to cell growth is mixed, there is plenty of evidence that activin A stimulates cell migration in various cell types including some in which it inhibits proliferation like intestinal epithelial cells [49] and colon cancer cells [44]. In addition to migration, also invasion and metastasis were reported to be enhanced by activin A in several tumor entities including prostate [50] and breast cancer [51], oral squamous cell carcinoma [52] and MPM [20]. Enhancement of cell migration and invasion by activin A was linked to the activation of distinct signaling molecules.…”

Prediction of cancer driver genes through network-based moment propagation of mutation scores

“…Five genes can be strongly linked to tumor relevant behavior and pathways. ACVR1B (also known as ALK4) is linked to tumorigenesis through its interaction with activin-A ( Kalli et al , 2019 ; Rautela et al , 2019 ). CASP10 inhibition leads to reduced apoptosis, while loss-of-function of RAP1A causes a reversion to a non-malignant phenotype in a model of invasive carcinoma ( Stammer et al , 2017 ).…”

Perspectives of small molecule inhibitors of activin receptor‑like kinase in anti‑tumor treatment and stem cell differentiation (Review)

“…Additionally, a recombinant activin A promoted the proliferation of lung cancer cell lines SKLU1 and H460 and the invasion of ovarian cancer cell lines OCC1 and SKOV-3 without affecting proliferation (45). Recent evidence has implicated overactive activin signaling in breast cancer cell lines, including MCF7 and MDA-MB231, and higher levels of p-Smad2, p-Smad3 and activin A in advanced breast cancer (46,47). Activin A also promotes invasion, angiogenesis, epithelial-mesenchymal transition (EMT) and stemness in breast cancer cells (46).…”