Targeting IL13Ralpha2 activates STAT6-TP63 pathway to suppress breast cancer lung metastasis

Abstract

IntroductionBasal-like breast cancer (BLBC) is an aggressive subtype often characterized by distant metastasis, poor patient prognosis, and limited treatment options. Therefore, the discovery of alternative targets to restrain its metastatic potential is urgently needed. In this study, we aimed to identify novel genes that drive metastasis of BLBC and to elucidate the underlying mechanisms of action.MethodsAn unbiased approach using gene expression profiling of a BLBC progression model and in silico leveraging of pre-existing tumor transcriptomes were used to uncover metastasis-promoting genes. Lentiviral-mediated knockdown of interleukin-13 receptor alpha 2 (IL13Ralpha2) coupled with whole-body in vivo bioluminescence imaging was performed to assess its role in regulating breast cancer tumor growth and lung metastasis. Gene expression microarray analysis was followed by in vitro validation and cell migration assays to elucidate the downstream molecular pathways involved in this process.ResultsWe found that overexpression of the decoy receptor IL13Ralpha2 is significantly enriched in basal compared with luminal primary breast tumors as well as in a subset of metastatic basal-B breast cancer cells. Importantly, breast cancer patients with high-grade tumors and increased IL13Ralpha2 levels had significantly worse prognosis for metastasis-free survival compared with patients with low expression. Depletion of IL13Ralpha2 in metastatic breast cancer cells modestly delayed primary tumor growth but dramatically suppressed lung metastasis in vivo. Furthermore, IL13Ralpha2 silencing was associated with enhanced IL-13-mediated phosphorylation of signal transducer and activator of transcription 6 (STAT6) and impaired migratory ability of metastatic breast cancer cells. Interestingly, genome-wide transcriptional analysis revealed that IL13Ralpha2 knockdown and IL-13 treatment cooperatively upregulated the metastasis suppressor tumor protein 63 (TP63) in a STAT6-dependent manner. These observations are consistent with increased metastasis-free survival of breast cancer patients with high levels of TP63 and STAT6 expression and suggest that the STAT6-TP63 pathway could be involved in impairing metastatic dissemination of breast cancer cells to the lungs.ConclusionOur findings indicate that IL13Ralpha2 could be used as a promising biomarker to predict patient outcome and provide a rationale for assessing the efficacy of anti-IL13Ralpha2 therapies in a subset of highly aggressive basal-like breast tumors as a strategy to prevent metastatic disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0607-y) contains supplementary material, which is available to authorized users.

PVT1‐derived miR‐1207‐5p promotes breast cancer cell growth by targeting STAT6

“…In breast cancer cells, STAT6 mediates IL4‐induced growth inhibition . Papageorgis et al . found that targeting interleukin 13 receptor subunit α2 (IL13Rα2) activated the STAT6 –tumor protein p63 pathway, which suppressed breast cancer lung metastasis.…”

Differential Expression Profiles of the Transcriptome in Breast Cancer Cell Lines Revealed by Next Generation Sequencing

“…The expression level of miR-210 in MDA-MB-231 cells is 4 times higher than that in MCF-7 cells in the present study. As its predicted target gene, STAT6 participates in stat6-tp63 pathway, which may be involved in inhibiting the metastasis of breast cancer cells to the lung [28]. Previous studies have shown that miR-210, compared with ER+ cells, was highly expressed in TNBC and was described as an independent prognostic factor of TNBC [29].…”

Tranilast-induced stress alleviation in solid tumors improves the efficacy of chemo- and nanotherapeutics in a size-independent manner

“…MCF10CA1a human breast cancer cell line was obtained from the Karmanos Cancer Institute (Detroit, MI, USA) and maintained as previously described35. 4T1 mouse mammary carcinoma cell line was purchased from ATCC and maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS).…”

“…Transverse 40 μm-thick tumor sections were produced using the Tissue-Tek Cryo3 (SAKURA) and immunostained with antibodies against collagen I, CD31 and hyaluronan. For Ki67 staining, tumors were fixed in paraformaldehyde and embedded in paraffin before sectioning35.…”