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Introduction Role of Bone morphogenetic protein 8A (BMP8A) and BMP receptors (BMPRs) in the tumourigenesis and progression of breast cancer remains elusive. Present study aims to investigate the expression of BMP8A and related BMPRs in breast cancer and their clinical implication. Method Expression of BMP8A and BMPRs was analysed using the RNA sequencing data of the TCGA breast cancer cohort. Findings were further validated in a meta gene array dataset (E-MDTA6703, n = 2302). STRING dataset was applied to explore the predicted receptors of BMP8A. Clinical relevance of deregulated BMP8A and BMPRs in breast cancer was assessed using both ANOVA and Kaplan-Meier tests. Correlation with markers of proliferation and invasion was evaluated using Spearman test. Result Analysis of datasets revealed that BMP8A and BMPR1B were highly expressed in breast cancer while ACVRL1, ACVR1, BMPR1A, ACVR1C, TGFBR2, TGFBR3, BMPR2 and ACVR2A were lower-expressed compared with normal controls. Expressions of BMPR1B, BMPR1A, BMPR2, ACVR2A and ACVR2B were highly correlated with BMP8A in the breast cancers. Overall survival in the group with higher BMP8A expression was shorter(median= 122.3 months), P = 0.012 compared with lower-expressed group(median = 215.2 months). No significant difference was observed in BMP8A and BMPRs in tumours according to their staging and lymph node involvement. Positive correlations were found between BMP8A and tumour proliferation, EMT, angiogenic markers. Conclusion BMP8A is increased in breast cancer and correlates with poor prognosis. The highly correlated BMPRs might be involved in the signal transduction of BMP8A to co-regulate BMP responsive genes and cellular functions which is yet to be investigated. Take-home Message BMP8A is increased in breast cancer and correlates with poor prognosis.

Diffuse intrinsic pontine gliomas (DIPG) are aggressive and highly treatment resistant pediatric tumors of the brainstem. The majority of the DIPG tumors (60-80%) carry somatic histone H3 mutations resulting in a global reduction of H3K27 trimethylation and subsequently a unique epigenetic landscape. Moreover, activating mutations in ACVR1 – the gene encoding for the BMP receptor ALK2 – were recently described in a large subset of DIPGs, suggestive of an oncogenic role of signaling from this receptor. Potential mechanisms of ACVR1-driven oncogenesis, however, remain poorly understood. Similar and overlapping ACVR1 mutations have been described in the rare disorder Fibrodysplasia Ossificans Progressiva (FOP), and evidence from FOP models have suggested several links between hypoxia signaling, BMP signaling, and FOP pathogenesis. We used cultured DIPG cells and adult glioma cells respectively to test the activity of the hypoxia pathway using a hypoxia-responsive elements (HRE)-luciferase reporter assay. Intriguingly, DIPG but not glioma cells overexpressing a mutant ACVR1 construct significantly elevated hypoxia signaling at hypoxia. BMP ligand stimulation resulted in a dose-dependent increase of hypoxia signaling in DIPG cells. By querying clinical gene expression data, we found elevated hypoxia signature scores in pediatric gliomas with mutant ACVR1 as compared to those with wildtype ACVR1. Finally, ACVR1 mutations frequently co-occur with Histone 3.3 and 3.1 mutations, and the hypoxia signature score was significantly higher than baseline only in tumors also harboring these Histone 3.3 or 3.1 mutations. Together, these data support the notion that hypoxia signaling is elevated downstream of ACVR1 specifically in pediatric gliomas and prompts for evaluation of hypoxia signaling as potential therapeutical target in DIPG.