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Hypoxia Selectively Enhances Integrin ?5?1 Receptor Expression in Breast Cancer to Promote Metastasis.

ABSTRACT: Metastasis is the leading cause of breast cancer mortality. Previous studies have implicated hypoxia-induced changes in the composition and stiffness of the extracellular matrix (ECM) in the metastatic process. Therefore, the contribution of potential ECM-binding receptors in this process was explored. Using a bioinformatics approach, the expression of all integrin receptor subunits, in two independent breast cancer patient datasets, were analyzed to determine whether integrin status correlates with a validated hypoxia-inducible gene signature. Subsequently, a large panel of breast cancer cell lines was used to validate that hypoxia induces the expression of integrins that bind to collagen (ITGA1, ITGA11, ITGB1) and fibronectin (ITGA5, ITGB1). Hypoxia-inducible factors (HIF-1 and HIF-2) are directly required for ITGA5 induction under hypoxic conditions, which leads to enhanced migration and invasion of single cells within a multicellular 3D tumor spheroid but did not affect migration in a 2D microenvironment. ITGB1 expression requires HIF-1?, but not HIF-2?, for hypoxic induction in breast cancer cells. ITGA5 (?5 subunit) is required for metastasis to lymph nodes and lungs in breast cancer models, and high ITGA5 expression in clinical biopsies is associated with an increased risk of mortality.Implications: These results reveal that targeting ITGA5 using inhibitors that are currently under consideration in clinical trials may be beneficial for patients with hypoxic tumors. Mol Cancer Res; 15(6); 723-34. ©2017 AACR.

SUBMITTER: Ju JA

PROVIDER: S-EPMC5510543 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Hypoxia Selectively Enhances Integrin α<sub>5</sub>β<sub>1</sub> Receptor Expression in Breast Cancer to Promote Metastasis.

Ju Julia A JA Godet Inês I Ye I Chae IC Byun Jungmin J Jayatilaka Hasini H Lee Sun Joo SJ Xiang Lisha L Samanta Debangshu D Lee Meng Horng MH Wu Pei-Hsun PH Wirtz Denis D Semenza Gregg L GL Gilkes Daniele M DM

Molecular cancer research : MCR 20170217 6

Metastasis is the leading cause of breast cancer mortality. Previous studies have implicated hypoxia-induced changes in the composition and stiffness of the extracellular matrix (ECM) in the metastatic process. Therefore, the contribution of potential ECM-binding receptors in this process was explored. Using a bioinformatics approach, the expression of all integrin receptor subunits, in two independent breast cancer patient datasets, were analyzed to determine whether integrin status correlates ...[more]

PMID: 28213554

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Project description: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.

Dataset Information

Hypoxia Selectively Enhances Integrin ?5?1 Receptor Expression in Breast Cancer to Promote Metastasis.

Publications

Hypoxia Selectively Enhances Integrin α<sub>5</sub>β<sub>1</sub> Receptor Expression in Breast Cancer to Promote Metastasis.

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