Genomic and transcriptomic profiling of inflammatory breast cancer reveals distinct molecular characteristics to non-inflammatory breast cancers.

PURPOSE: Inflammatory breast cancer (IBC), a rare and highly aggressive form of breast cancer, accounts for 10% of breast cancer-related deaths. Previous omics studies of IBC have focused solely on one of genomics or transcriptomics and did not discover common differences that could distinguish IBC from non-IBC. METHODS: Seventeen IBC patients and five non-IBC patients as well as additional thirty-three Asian breast cancer samples from TCGA-BRCA were included for the study. We performed whole-exon sequencing (WES) to investigate different somatic genomic alterations, copy number variants, and large structural variants between IBC and non-IBC. Bulk RNA sequencing (RNA-seq) was performed to examine the differentially expressed genes, pathway enrichment, and gene fusions. WES and RNA-seq data were further investigated in combination to discover genes that were dysregulated in both genomics and transcriptomics. RESULTS: Copy number variation analysis identified 10 cytobands that showed higher frequency in IBC. Structural variation analysis showed more frequent deletions in IBC. Pathway enrichment and immune infiltration analysis indicated increased immune activation in IBC samples. Gene fusions including CTSC-RAB38 were found to be more common in IBC. We demonstrated more commonly dysregulated RAS pathway in IBC according to both WES and RNA-seq. Inhibitors targeting RAS signaling and its downstream pathways were predicted to possess promising effects in IBC treatment. CONCLUSION: We discovered differences unique in Asian women that could potentially explain IBC etiology and presented RAS signaling pathway as a potential therapeutic target in IBC treatment.

Efficient removal of organic pollutants by activation of peroxydisulfate with the magnetic CoFe2O4/carbon nanotube composite.

A magnetic composite of CoFe2O4 and carbon nanotube (CNT) was prepared using the solvothermal approach and then employed for the activation of peroxydisulfate (PDS) to degrade reactive black 5 (RB5) and other organic pollutants. Characterization results of the composite catalyst revealed the successful loading of spherical CoFe2O4 particles on CNTs, possessing abundant porosity as well as magnetic separation capability. Under the degradation conditions of 0.2 g/L CoFe2O4-CNT dosage and 4 mM PDS dosage, the removal efficiencies of 10 mg/L RB5 and other pollutants were in the range of 94.5 to ~ 100%. The effects of pH, co-existing ions/humic acid, and water matrices as well as the reusability of the catalyst were also investigated in detail. Furthermore, the degradation mechanism and pathway were proposed based on quenching experiments, LC-MS analysis, and density functional theory (DFT) calculations, and the toxicity of the degradation products was evaluated in the quantitative structure-activity relationship approach.

Thyroid disrupting effects and the developmental toxicity of hexafluoropropylene oxide oligomer acids in zebrafish during early development.

As perfluorooctanoic acid (PFOA) alternatives, hexafluoropropylene oxide dimeric acid (HFPO-DA) and hexafluoropropylene oxide trimeric acid (HFPO-TA) have been increasingly used and caused considerable water pollution. However, their toxicities to aquatic organisms are still not well known. Therefore, in this study, zebrafish embryos were exposed to PFOA (0, 1.5, 3 and 6 mg/L), HFPO-DA (0, 3, 6 and 12 mg/L) and HFPO-TA (0, 1, 2 and 4 mg/L) to comparatively investigate their thyroid disrupting effects and the developmental toxicity. Results demonstrated that waterborne exposure to PFOA and its two alternatives decreased T4 contents, the heart rate and swirl-escape rate of zebrafish embryos/larvae. The transcription levels of genes related to thyroid hormone regulation (crh), biosynthesis (tpo and tg), function (trα and trß), transport (transthyretin, ttr), and metabolism (dio1, dio2 and ugt1ab), were differently altered after the exposures, which induced the thyroid disrupting effects and decreased the heart rate. In addition, the transcription levels of some genes related to the nervous system development were also significantly affected, which was associated with the thyroid disrupting effects and consequently affected the locomotor activity of zebrafish. Therefore, HFPO-DA and HFPO-TA could not be safe alternatives to PFOA. Further studies to uncover the underlying mechanisms of these adverse effects are warranted.

A Subpopulation of Luminal Progenitors Secretes Pleiotrophin to Promote Angiogenesis and Metastasis in Inflammatory Breast Cancer.

Inflammatory breast cancer (IBC) is a highly aggressive subtype of breast cancer characterized by rapidly arising diffuse erythema and edema. Genomic studies have not identified consistent alterations and mechanisms that differentiate IBC from non-IBC tumors, suggesting that the microenvironment could be a potential driver of IBC phenotypes. Here, using single-cell RNA sequencing, multiplex staining, and serum analysis in patients with IBC, we identified enrichment of a subgroup of luminal progenitor (LP) cells containing high expression of the neurotropic cytokine pleiotrophin (PTN) in IBC tumors. PTN secreted by the LP cells promoted angiogenesis by directly interacting with the NRP1 receptor on endothelial tip cells located in both IBC tumors and the affected skin. NRP1 activation in tip cells led to recruitment of immature perivascular cells in the affected skin of IBC, which are correlated with increased angiogenesis and IBC metastasis. Together, these findings reveal a role for cross-talk between LPs, endothelial tip cells, and immature perivascular cells via PTN-NRP1 axis in the pathogenesis of IBC, which could lead to improved strategies for treating IBC. SIGNIFICANCE: Nonmalignant luminal progenitor cells expressing pleiotrophin promote angiogenesis by activating NRP1 and induce a prometastatic tumor microenvironment in inflammatory breast cancer, providing potential therapeutic targets for this aggressive breast cancer subtype.

Sequential versus concurrent adjuvant chemo-endocrine therapy for HR+ early breast cancer: a systematic review and Bayesian network meta-analysis.

Background: Chemo-endocrine therapy is the standard adjuvant treatment strategy for hormone receptor-positive (HR+) early breast cancer. Our research aimed to compare the efficacy of adjuvant chemo-endocrine therapies, regarding different endocrinal regimens and integration sequences (sequential or concomitant), for HR+ early breast cancer. Methods: PubMed, Embase, the Cochrane Library and web of science were searched for articles published before October 2018 with Clinicaltrials.gov (https://clinicaltrials.gov) for registered clinical trials and ASCO, AACR, ESCO, SABCS meeting abstracts for addition. Randomized clinical trials (RCTs) comparing chemotherapy and/or endocrine therapy in the adjuvant treatment of primary breast cancer patients were included. Hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS) were extracted and analyzed in Bayesian analysis. Patients were stratified by menopause status. Results: Thirty-three trials with 28,515 patients and 19 treatments were enrolled. Comparisons between regimens has seen better efficacy of ovarian function suppressor (OFS) + aromatase inhibitors (AI) than OFS + tamoxifen, either used concurrently [HR =0.69, 95% credible intervals (CrI): 0.47-1.02] or sequentially with chemotherapy (HR =0.72, 95% CrI: 0.49-1.06) in premenopausal patients. Adding OFS to tamoxifen was marginally better than tamoxifen used alone (DFS: HR =0.85, 95% CrI: 0.65-1.09; OS: HR =0.77, 95% CrI: 0.52-1.08). Comparisons between different sequences of chemo-endocrine therapy proved equal efficacy in premenopausal and postmenopausal patients. Recommendation was given based on ranking of treatments. Sequential and concurrent use of chemotherapy and OFS + AI ranked equally in premenopausal patients and were recommended as the best option. However, tamoxifen ranked higher when used concurrently with chemotherapy in both premenopausal and postmenopausal HR+ early breast cancer. Conclusions: In the adjuvant chemo-endocrine therapy for premenopausal HR+ early breast cancer, concurrent and sequential adjuvant chemo-endocrine therapy was demonstrated of equal efficacy in both postmenopausal and premenopausal HR+ early breast cancer. Trial Registration: PROSPERO CRD42018104889.