Activin-A signaling promotes epithelial–mesenchymal transition, invasion, and metastatic growth of breast cancer (original) (raw)
Related papers
Serum and Tissue Expression of Activin A in Postmenopausal Women with Breast Cancer
The Journal of Clinical Endocrinology & Metabolism, 2002
The aim of the present study was to evaluate 1) whether breast cancer expresses activin A subunit mRNA, 2) whether serum activin A levels are altered in postmenopausal women with breast cancer, and 3) how circulating activin A levels change after tumor removal. Four groups of women (n ؍ 158) were enrolled for the present prospective study: two groups were composed of postmenopausal women with breast cancer (n ؍ 74) or benign lesions (n ؍ 15); the third was a control group composed of healthy postmenopausal women (n ؍ 62); and the fourth group included healthy fertile women (n ؍ 7) undergoing plastic surgery with removal of non-neoplastic mammary tissue.
Activin A Signaling Regulates IL13Rα2 Expression to Promote Breast Cancer Metastasis
Frontiers in Oncology
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 contextdepended 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?
Expert Opinion on Therapeutic Targets
Introduction: Activin A is involved in the regulation of a surprisingly broad number of processes that are relevant for cancer development and treatment; it is implicated in cell autonomous functions and multiple regulatory functions in the tumor microenvironment. Areas covered: This article summarizes the current knowledge about activin A in cell growth and death, migration and metastasis, angiogenesis, stemness and drug resistance, regulation of antitumor immunity, and cancer cachexia. We explore the role of activin A as a biomarker and discuss strategies for using it as target for cancer therapy. Literature retrieved from Medline until 25 June 2020 was considered. Expert opinion: While many functions of activin A were investigated in preclinical models, there is currently limited experience from clinical trials. Activin A has growth-and migration-promoting effects, contributes to immune evasion and cachexia and is associated with shorter survival in several cancer types. Targeting activin A could offer the chance to simultaneously limit tumor growth and spreading, improve drug response, boost antitumor immune responses and improve cancer-associated or treatment-associated cachexia, bone loss, and anemia. Nevertheless, defining which patients have the highest likelihood of benefiting from these effects is challenging and will require further work.
Activin B and Activin C Have Opposing Effects on Prostate Cancer Progression and Cell Growth
Cancers
Current prognostic and diagnostic tests for prostate cancer are not able to accurately distinguish between aggressive and latent cancer. Members of the transforming growth factor-β (TGFB) family are known to be important in regulating prostate cell growth and some have been shown to be dysregulated in prostate cancer. Therefore, the aims of this study were to examine expression of TGFB family members in primary prostate tumour tissue and the phenotypic effect of activins on prostate cell growth. Tissue cores of prostate adenocarcinoma and normal prostate were immuno-stained and protein expression was compared between samples with different Gleason grades. The effect of exogenous treatment with, or overexpression of, activins on prostate cell line growth and migration was examined. Activin B expression was increased in cores containing higher Gleason patterns and overexpression of activin B inhibited growth of PNT1A cells but increased growth and migration of the metastatic PC3 cells...
Cancer research, 1996
Activin is a member of the transforming growth factor beta superfamily, which is known to have activities involved in regulating differentiation and development. By using reverse transcription-PCR analysis on immunoaffinity-purified human breast cells, we have found that activin beta a and activin type II receptor are expressed by myoepithelial cells, whereas no expression was detected in other breast cell types. In examining 15 breast cell lines, we have found only four (HBL-100, MCF10-A, PMC-42, and BT 20) to be positive for activin beta a mRNA, whereas all expressed the activin type II receptor. Furthermore, we have found activin A to be a potent growth inhibitor of MCF- 7 cells (at 2 ng/ml), where it causes an arrest in G(1). Activin A does not appear to have an effect on the cell cycle of primary myoepithelial or luminal cells. However, we demonstrate that activin is an inhibitor of tubule formation by human mammary organoids in vitro. These are the first observations of activi...
Activin A balance regulates epithelial invasiveness and tumorigenesis
Laboratory investigation; a journal of technical methods and pathology, 2014
Activin A (Act A) is a member of the TGFβ superfamily. Act A and TGFβ have multiple common downstream targets and have been described to merge in their intracellular signaling cascades and function. We have previously demonstrated that coordinated loss of E-cadherin and TGFβ receptor II (TβRII) results in epithelial cell invasion. When grown in three-dimensional organotypic reconstruct cultures, esophageal keratinocytes expressing dominant-negative mutants of E-cadherin and TβRII showed activated Smad2 in the absence of functional TβRII. However, we could show that increased levels of Act A secretion was able to induce Smad2 phosphorylation. Growth factor secretion can activate autocrine and paracrine signaling, which affects crosstalk between the epithelial compartment and the surrounding microenvironment. We show that treatment with the Act A antagonist Follistatin or with a neutralizing Act A antibody can increase cell invasion in organotypic cultures in a fibroblast- and MMP-dep...
Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells
British Journal of Cancer, 2012
BACKGROUND: Activins control the growth of several tumour types including thoracic malignancies. In the present study, we investigated their expression and function in malignant pleural mesothelioma (MPM). METHODS: The expression of activins and activin receptors was analysed by quantitative PCR in a panel of MPM cell lines. Activin A expression was further analysed by immunohistochemistry in MPM tissue specimens (N ¼ 53). Subsequently, MPM cells were treated with activin A, activin receptor inhibitors or activin-targeting siRNA and the impact on cell viability, proliferation, migration and signalling was assessed. RESULTS: Concomitant expression of activin subunits and receptors was found in all cell lines, and activin A was overexpressed in most cell lines compared with non-malignant mesothelial cells. Similarly, immunohistochemistry demonstrated intense staining of tumour cells for activin A in a subset of patients. Treatment with activin A induced SMAD2 phosphorylation and stimulated clonogenic growth of mesothelioma cells. In contrast, treatment with kinase inhibitors of activin receptors (SB-431542, A-8301) inhibited MPM cell viability, clonogenicity and migration. Silencing of activin A expression by siRNA oligonucleotides further confirmed these results and led to reduced cyclin D1/3 expression. CONCLUSION: Our study suggests that activin A contributes to the malignant phenotype of MPM cells via regulation of cyclin D and may represent a valuable candidate for therapeutic interference.