Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair.

Drugs targeting the DNA damage response (DDR) are widely used in cancer therapy, but resistance to these drugs remains a major clinical challenge. Here, we show that SYCP2, a meiotic protein in the synaptonemal complex, is aberrantly and commonly expressed in breast and ovarian cancers and associated with broad resistance to DDR drugs. Mechanistically, SYCP2 enhances the repair of DNA double-strand breaks (DSBs) through transcription-coupled homologous recombination (TC-HR). SYCP2 promotes R-loop formation at DSBs and facilitates RAD51 recruitment independently of BRCA1. SYCP2 loss impairs RAD51 localization, reduces TC-HR, and renders tumors sensitive to PARP and topoisomerase I (TOP1) inhibitors. Furthermore, our studies of two clinical cohorts find that SYCP2 overexpression correlates with breast cancer resistance to antibody-conjugated TOP1 inhibitor and ovarian cancer resistance to platinum treatment. Collectively, our data suggest that SYCP2 confers cancer cell resistance to DNA-damaging agents by stimulating R-loop-mediated DSB repair, offering opportunities to improve DDR therapy.

Surgical management of nervus intermedius neuralgia: A report of 4 cases and literature review.

BACKGROUND: Nervus intermedius neuralgia (NIN) is characterized by paroxysmal episodes of sharp, lancinating pain in the deep ear. Unfortunately, only a few studies exist in the literature on this pain syndrome, its pathology and postoperative outcomes. METHOD: We conducted a retrospective review of four cases diagnosed with NIN who underwent a neurosurgical intervention at our center from January 2015 to January 2023. Detailed information on their MRI examinations, intraoperative findings and other clinical presentations were obtained, and the glossopharyngeal and vagus nerves were isolated for immunohistochemistry examination. RESULTS: A total of 4 NIN patients who underwent a microsurgical intervention at our institution were included in this report. The NI was sectioned in all patients and 3 of them underwent a microvascular decompression. Of these 4 patients, 1 had a concomitant trigeminal neuralgia (TN), and 1 a concomitant glossopharyngeal neuralgia (GPN). Three patients underwent treatment for TN and 2 for GPN. Follow-up assessments ranged from 8 to 99 months. Three patients reported complete pain relief immediately after the surgery until last follow-up, while in the remaining patient the preoperative pain gradually resolved over the 3 month period. Immunohistochemistry revealed that a greater amount of CD4+ and CD8+ T cells had infiltrated the glossopharyngeal versus vagus nerve. CONCLUSIONS: NIN is an extremely rare condition showing a high degree of overlap with TN/GPN. An in depth neurosurgical intervention is effective to completely relieve NIN pain, without any serious complications. It appears that T cells may play regulatory role in the pathophysiology of CN neuralgia.

Intragenic Rearrangement Burden Associates with Immune Cell Infiltration and Response to Immune Checkpoint Blockade in Cancer.

Immune checkpoint blockade (ICB) can induce durable cancer remission. However, only a small subset of patients gains benefits. While tumor mutation burden (TMB) differentiates responders from nonresponders in some cases, it is a weak predictor in tumor types with low mutation rates. Thus, there is an unmet need to discover a new class of genetic aberrations that predict ICB responses in these tumor types. Here, we report analyses of pan-cancer whole genomes which revealed that intragenic rearrangement (IGR) burden is significantly associated with immune infiltration in breast, ovarian, esophageal, and endometrial cancers, particularly with increased M1 macrophage and CD8+ T-cell signatures. Multivariate regression against spatially counted tumor-infiltrating lymphocytes in breast, endometrial, and ovarian cancers suggested that IGR burden is a more influential covariate than other genetic aberrations in these cancers. In the MEDI4736 trial evaluating durvalumab in esophageal adenocarcinoma, IGR burden correlated with patient benefits. In the IMVigor210 trial evaluating atezolizumab in urothelial carcinoma, IGR burden increased with platinum exposure and predicted patient benefit among TMB-low, platinum-exposed tumors. Altogether, we have demonstrated that IGR burden correlates with T-cell inflammation and predicts ICB benefit in TMB-low, IGR-dominant tumors, and in platinum-exposed tumors.

iGenSig-Rx: an integral genomic signature based white-box tool for modeling cancer therapeutic responses using multi-omics data.

Multi-omics sequencing is expected to become clinically routine within the next decade and transform clinical care. However, there is a paucity of viable and interpretable genome-wide modeling methods that can facilitate rational selection of patients for tailored intervention. Here we develop an integral genomic signature-based method called iGenSig-Rx as a white-box tool for modeling therapeutic response based on clinical trial datasets with improved cross-dataset applicability and tolerance to sequencing bias. This method leverages high-dimensional redundant genomic features to address the challenges of cross-dataset modeling, a concept similar to the use of redundant steel rods to reinforce the pillars of a building. Using genomic datasets for HER2 targeted therapies, the iGenSig-Rx model demonstrates stable predictive power across four independent clinical trials. More importantly, the iGenSig-Rx model offers the level of transparency much needed for clinical application, allowing for clear explanations as to how the predictions are produced, how the features contribute to the prediction, and what are the key underlying pathways. We expect that iGenSig-Rx as a class of biologically interpretable multi-omics modeling methods will have broad applications in big-data based precision oncology. The R package is available: https://github.com/wangxlab/iGenSig-Rx. NOTE: the Github website will be released upon publication and the R package is available for review through google drive: https://drive.google.com/drive/folders/1KgecmUoon9-h2Dg1rPCyEGFPOp28Ols3?usp=sharing.

IndepthPathway: an integrated tool for in-depth pathway enrichment analysis based on single-cell sequencing data.

MOTIVATION: Single-cell sequencing enables exploring the pathways and processes of cells, and cell populations. However, there is a paucity of pathway enrichment methods designed to tolerate the high noise and low gene coverage of this technology. When gene expression data are noisy and signals are sparse, testing pathway enrichment based on the genes expression may not yield statistically significant results, which is particularly problematic when detecting the pathways enriched in less abundant cells that are vulnerable to disturbances. RESULTS: In this project, we developed a Weighted Concept Signature Enrichment Analysis specialized for pathway enrichment analysis from single-cell transcriptomics (scRNA-seq). Weighted Concept Signature Enrichment Analysis took a broader approach for assessing the functional relations of pathway gene sets to differentially expressed genes, and leverage the cumulative signature of molecular concepts characteristic of the highly differentially expressed genes, which we termed as the universal concept signature, to tolerate the high noise and low coverage of this technology. We then incorporated Weighted Concept Signature Enrichment Analysis into an R package called "IndepthPathway" for biologists to broadly leverage this method for pathway analysis based on bulk and single-cell sequencing data. Through simulating technical variability and dropouts in gene expression characteristic of scRNA-seq as well as benchmarking on a real dataset of matched single-cell and bulk RNAseq data, we demonstrate that IndepthPathway presents outstanding stability and depth in pathway enrichment results under stochasticity of the data, thus will substantially improve the scientific rigor of the pathway analysis for single-cell sequencing data. AVAILABILITY AND IMPLEMENTATION: The IndepthPathway R package is available through: https://github.com/wangxlab/IndepthPathway.

Giant myxofibrosarcoma of the esophagus treated by endoscopic submucosal dissection: A case report.

BACKGROUND: Myxofibrosarcoma (MFS) is a fibroblast-derived sarcoma that mainly occurs in subcutaneous tissue. MFS rarely occurs in the gastrointestinal tract, especially in the esophagus. CASE SUMMARY: A 79-year-old male patient was admitted to our hospital for dysphagia for a week. Computed tomography and electronic gastroscopy showed that a giant mass was located 30 cm from the incisor and extended to the cardia. There was incomplete esophageal stenosis. Endoscopic pathology showed spindle cell lesions, which were considered inflammatory myofibroblast like hyperplasia. Considering the strong demands of the patient and his family, and the fact that most inflammatory myofibroblast tumors are benign, we decided to perform endoscopic submucosal dissection (ESD) even if the tumor size was giant (9.0 cm × 3.0 cm). Postoperative pathological examination resulted in a final diagnosis of MFS. MFS rarely occurs in the gastrointestinal tract, especially in the esophagus. Surgical resection and local adjuvant radiotherapy are the first choices to improve the prognosis. This case report firstly described the ESD for esophageal giant MFS. It suggests that ESD may be an alternative treatment for primary esophageal MFS. CONCLUSION: This case report for the first time describe the successful treatment of a giant esophageal MFS by ESD, suggesting that ESD may be an alternative treatment for primary esophageal MFS, especially in elderly high-risk patients with obvious dysphagia symptoms.

Mesenchymal stem cells shuttling miR-503 via extracellular vesicles enhance glioma immune escape.

Glioma is emerging as an aggressive type of glioma characterized by invasive growth pattern and dismal oncologic outcomes. microRNAs (miRNAs) have been attracting research attention in tumorigenesis. Herein, the aim of the current investigation was to explore the functional role of mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) containing miR-503 in glioma. The glioma tissues and corresponding normal brain tissues were collected from patients with glioma, followed by quantification of miR-503, kinesin family member 5A (KIF5A) and interleukin-7 (IL-7). EVs were isolated from bone marrow MSCs and identified by transmission electron microscope and nanoparticle tracking analysis. EVs from miR-503 mimic-transfected MSCs, miR-503 agomir,, oe-KIF5A, or sh-IL-7 was delivered into glioma cells to determine their effects on biological behaviors of glioma and T cells as well as the release of immunosuppressive factors. Lastly, a mouse model of glioma was developed to validate the function in vivo. miR-503 was expressed at a high level in glioma tissues while KIF5A was poorly expressed and targeted by miR-503. Furthermore, miR-503 loaded in MSC-EVs or upregulated miR-503 was demonstrated to facilitate glioma cell proliferation, migration and invasion accompanied by promoted release of immunosuppressive factors. Effects of overexpressed KIF5A on T cell behavior modulation were dependent on the IL-7 signaling pathway. Such results were reproduced in mice with glioma. Collectively, the discovery of miR-503 incorporated in MSC-EVs being a regulator that controls immune escape in glioma provides a novel molecular insight that holds promises to develop therapeutic strategies against glioma.

An integral genomic signature approach for tailored cancer therapy using genome-wide sequencing data.

Low-cost multi-omics sequencing is expected to become clinical routine and transform precision oncology. Viable computational methods that can facilitate tailored intervention while tolerating sequencing biases are in high demand. Here we propose a class of transparent and interpretable computational methods called integral genomic signature (iGenSig) analyses, that address the challenges of cross-dataset modeling through leveraging information redundancies within high-dimensional genomic features, averaging feature weights to prevent overweighing, and extracting unbiased genomic information from large tumor cohorts. Using genomic dataset of chemical perturbations, we develop a battery of iGenSig models for predicting cancer drug responses, and validate the models using independent cell-line and clinical datasets. The iGenSig models for five drugs demonstrate predictive values in six clinical studies, among which the Erlotinib and 5-FU models significantly predict therapeutic responses in three studies, offering clinically relevant insights into their inverse predictive signature pathways. Together, iGenSig provides a computational framework to facilitate tailored cancer therapy based on multi-omics data.

Fusion-associated carcinomas of the breast: Diagnostic, prognostic, and therapeutic significance.

Recurrent gene fusions comprise a class of viable genetic targets in solid tumors that have culminated several recent breakthrough cancer therapies. Their role in breast cancer, however, remains largely underappreciated due to the complexity of genomic rearrangements in breast malignancy. Just recently, we and others have identified several recurrent gene fusions in breast cancer with important clinical and biological implications. Examples of the most significant recurrent gene fusions to date include (1) ESR1::CCDC170 gene fusions in luminal B and endocrine-resistant breast cancer that exert oncogenic function via modulating the HER2/HER3/SRC Proto-Oncogene (SRC) complex, (2) ESR1 exon 6 fusions in metastatic disease that drive estrogen-independent estrogen-receptor transcriptional activity, (3) BCL2L14::ETV6 fusions in a more aggressive form of the triple-negative subtype that prime epithelial-mesenchymal transition and endow paclitaxel resistance, (4) the ETV6::NTRK3 fusion in secretory breast carcinoma that constitutively activates NTRK3 kinase, (5) the oncogenic MYB-NFIB fusion as a genetic driver underpinning adenoid cystic carcinomas of the breast that activates MYB Proto-Oncogene (MYB) pathway, and (6) the NOTCH/microtubule-associated serine-threonine (MAST) kinase gene fusions that activate NOTCH and MAST signaling. Importantly, these fusions are enriched in more aggressive and lethal breast cancer presentations and appear to confer therapeutic resistance. Thus, these gene fusions could be utilized as genetic biomarkers to identify patients who require more intensive treatment and surveillance. In addition, kinase fusions are currently being evaluated in breast cancer clinical trials and ongoing mechanistic investigation is exposing therapeutic vulnerabilities in patients with fusion-positive disease.

Lack of Association Between Helicobacter pylori Infection and the Risk of Thyroid Nodule Types: A Multicenter Case-Control Study in China.

The prevalence of Helicobacter pylori infection is high worldwide, while numerous research has focused on unraveling the relationship between H. pylori infection and extragastric diseases. Although H. pylori infection has been associated with thyroid diseases, including thyroid nodule (TN), the relationship has mainly focused on potential physiological mechanisms and has not been validated by large population epidemiological investigations. Therefore, we thus designed a case-control study comprising participants who received regular health examination between 2017 and 2019. The cases and controls were diagnosed via ultrasound, while TN types were classified according to the guidelines of the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS). Moreover, H. pylori infection was determined by C14 urea breath test, while its relationship with TN type risk and severity was analyzed using binary and ordinal logistic regression analyses. A total of 43,411 participants, including 13,036 TN patients and 30,375 controls, were finally recruited in the study. The crude odds ratio (OR) was 1.07 in Model 1 (95% CI = 1.03-1.14) without adjustment compared to the H. pylori non-infection group. However, it was negative in Model 2 (OR = 1.02, 95% CI = 0.97-1.06) after being adjusted for gender, age, body mass index (BMI), and blood pressure and in Model 3 (OR = 1.01, 95% CI = 0.97-1.06) after being adjusted for total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein on the basis of Model 2. Control variables, including gender, age, BMI, and diastolic pressure, were significantly correlated with the risk of TN types. Additionally, ordinal logistic regression results revealed that H. pylori infection was positively correlated with malignant differentiation of TN (Model 1: OR = 1.06, 95% CI = 1.02-1.11), while Model 2 and Model 3 showed negative results (Model 2: OR = 1.01, 95% CI = 0.96-1.06; Model 3: OR = 1.01, 95% CI = 0.96-1.05). In conclusion, H. pylori infection was not significantly associated with both TN type risk and severity of its malignant differentiation. These findings provide relevant insights for correcting possible misconceptions regarding TN type pathogenesis and will help guide optimization of therapeutic strategies for thyroid diseases.

Short-Term Clinical Efficacy of Neoadjuvant Chemotherapy Combined With Laparoscopic Gastrectomy for Locally Advanced Siewert Type II and III Adenocarcinoma of the Esophagogastric Junction: A Retrospective, Propensity Score-Matched Study.

BACKGROUND: Laparoscopic gastrectomy (LG) has been increasingly used for the treatment of locally advanced Siewert type II and III adenocarcinoma of the esophagogastric junction (AEG). However, whether LG can achieve the same short-term efficacy in the treatment of patients who receive neoadjuvant chemotherapy (NACT) remains controversial. Thus, the aim of this study was to investigate the clinical outcomes of NACT combined with LG for Siewert type II and III AEG. METHODS: This retrospective study identified patients with locally advanced Siewert type II and III AEG diagnosed between May 2011 and October 2020 using the clinical tumor-node-metastasis (cTNM) staging system. The short-term outcomes were compared between the matched groups using a 1:3 propensity score matching (PSM) method, which was performed to reduce bias in patient selection. RESULTS: After PSM, 164 patients were selected, including 41 in the NACT group and 123 in the LG group. The baseline characteristics were similar between the two groups. Compared with the LG group, the NACT group exhibit a smaller tumor size and significantly less advanced pathological tumor classification and nodal classification stages. The time to first flatus of the NACT group was significantly shorter, but the hospital stay was significantly longer than that of the LG group. The NACT group showed similar overall (29.3% vs 25.2%, P=0.683), systemic (24.4% vs 21.1%, P=0.663), local (12.2% vs 9.8%, P=0.767), minor (19.5% vs 19.5%, P=1.000) and major (9.8% vs 5.7%, P=0.470) complications as the LG group. Subgroup analyses showed no significant differences in most stratified parameters. Operation time≥ 300 minutes was identified as an independent risk factor for overall complications. Age≥ 60 years was identified as an independent risk factor for major complications. CONCLUSION: NACT combined with LG for AEG does not increase the risk of postoperative morbidity and mortality compared with LG.

Artificial neural networks modeling for lead removal from aqueous solutions using iron oxide nanocomposites from bio-waste mass.

Heavy metal ions in aqueous solutions are taken into account as one of the most harmful environmental issues that ominously affect human health. Pb(II) is a common pollutant among heavy metals found in industrial wastewater, and various methods were developed to remove the Pb(II). The adsorption method was more efficient, cheap, and eco-friendly to remove the Pb(II) from aqueous solutions. The removal efficiency depends on the process parameters (initial concentration, the adsorbent dosage of T-Fe3O4 nanocomposites, residence time, and adsorbent pH). The relationship between the process parameters and output is non-linear and complex. The purpose of the present study is to develop an artificial neural networks (ANN) model to estimate and analyze the relationship between Pb(II) removal and adsorption process parameters. The model was trained with the backpropagation algorithm. The model was validated with the unseen datasets. The correlation coefficient adj.R2 values for total datasets is 0.991. The relationship between the parameters and Pb(II) removal was analyzed by sensitivity analysis and creating a virtual adsorption process. The study determined that the ANN modeling was a reliable tool for predicting and optimizing adsorption process parameters for maximum lead removal from aqueous solutions.

Reversible Transformation between Azo and Azonium Bond Other than Photoisomerization of Azo Bond in Main-Chain Polyazobenzenes.

Although side-chain polyazobenzenes have been extensively studied, main-chain polyazobenzenes (abbreviated MCPABs) are rarely reported due to the challenges associated with difficulty in synthetic chemistry and photoisomerization of azo bonds in MCPABs. Thus, it is highly demanded to develop new mechanisms other than photoisomerization of azo bonds in MCPABs to extend their applications. In this work, we created a new series of N-linked MCPABs via fast NaBH4-mediated reductive coupling polymerization on N-substituted bis(4-nitrophenyl)amines. The structure of MCPABs has been characterized by comprehensive solid-state NMR experiments such as CPMAS 13C NMR with long and short contact times, cross-polarization polarization-inversion (CPPI), and cross-polarization nonquaternary suppressed (CPNQS). The azo bonds in MCPABs were found to be promising for acid vapor sensing, being acidified to form azonium ion with significant color change from red to green. And the azonium of MCPABs turned from green to red when exposed to base vapor, thus suitable for base vapor sensing.

Therapeutic Targeting of Nemo-like Kinase in Primary and Acquired Endocrine-resistant Breast Cancer.

PURPOSE: Endocrine resistance remains a major clinical challenge in estrogen receptor (ER)-positive breast cancer. Despite the encouraging results from clinical trials for the drugs targeting known survival signaling, relapse is still inevitable. There is an unmet need to discover new drug targets in the unknown escape pathways. Here, we report Nemo-like kinase (NLK) as a new actionable kinase target that endows previously uncharacterized survival signaling in endocrine-resistant breast cancer. EXPERIMENTAL DESIGN: The effects of NLK inhibition on the viability of endocrine-resistant breast cancer cell lines were examined by MTS assay. The effect of VX-702 on NLK activity was verified by kinase assay. The modulation of ER and its coactivator, SRC-3, by NLK was examined by immunoprecipitation, kinase assay, luciferase assay, and RNA sequencing. The therapeutic effects of VX-702 and everolimus were tested on cell line- and patient-derived xenograft (PDX) tumor models. RESULTS: NLK overexpression endows reduced endocrine responsiveness and is associated with worse outcome of patients treated with tamoxifen. Mechanistically, NLK may function, at least in part, via enhancing the phosphorylation of ERα and its key coactivator, SRC-3, to modulate ERα transcriptional activity. Through interrogation of a kinase profiling database, we uncovered and verified a highly selective dual p38/NLK inhibitor, VX-702. Coadministration of VX-702 with the mTOR inhibitor, everolimus, demonstrated a significant therapeutic effect in cell line-derived xenograft and PDX tumor models of acquired or de novo endocrine resistance. CONCLUSIONS: Together, this study reveals the potential of therapeutic modulation of NLK for the management of the endocrine-resistant breast cancers with active NLK signaling.

A Novel Neoplastic Fusion Transcript, RAD51AP1-DYRK4, Confers Sensitivity to the MEK Inhibitor Trametinib in Aggressive Breast Cancers.

PURPOSE: Luminal B breast tumors are more aggressive estrogen receptor-positive (ER+) breast cancers characterized by aggressive clinical behavior and a high risk of metastatic dissemination. The underlying pathologic molecular events remain poorly understood with a paucity of actionable genetic drivers, which hinders the development of new treatment strategies. EXPERIMENTAL DESIGN: We performed large-scale RNA sequencing analysis to identify chimerical transcripts preferentially expressed in luminal B breast cancer. The lead candidate was validated by reverse transcription PCR in breast cancer tissues. The effects of inducible ectopic expression or genetic silencing were assessed by phenotypic assays such as MTS, transwell, and transendothelial migration assays, and by clonogenic assays to assess MEK inhibitor sensitivity. Subcellular fractionation, Western blots, and immunoprecipitation were performed to characterize the protein products and elucidate the engaged mechanisms. RESULTS: Here we report a novel tumor-specific chimeric transcript RAD51AP1-DYRK4 preferentially expressed in luminal B tumors. Analysis of 200 ER+ breast tumors detected RAD51AP1-DYRK4 overexpression in 19 tumors (9.5%), which is markedly enriched in the luminal B tumors (17.5%). Ectopic expression of RAD51AP1-DYRK4, but not wild-type RAD51AP1, leads to marked activation of MEK/ERK signaling, and endows increased cell motility and transendothelial migration. More importantly, RAD51AP1-DYRK4 appears to endow increased sensitivity to the MEK inhibitor trametinib through attenuating compensatory activation of HER2/PI3K/AKT under MEK inhibition. CONCLUSIONS: This discovery sheds light on a new area of molecular pathobiology of luminal B tumors and implies potential new therapeutic opportunities for more aggressive breast tumors overexpressing this fusion.

Vesicular Membrane with Structured Interstitial Water.

Self-assembled vesicles with structured (tetrahedral order with strong hydrogen bonds) interstitial water are reported. The vesicles, known as MCsome, are assembled from metal carbonyl compounds, FpR (Fp = (Cp)Fe(PPh3)(CO)(CO-), Cp = cyclopentadiene, R = C3Bithiophene, C6Pyrene or C6) with the Fp heads exposed to water. The R groups are surrounded by the interstitial water with the hydrogen bonding strength variable depending on the hydrophobicity of R groups. The structure of the interstitial water is responsible for the integrity of the membrane and swelling behavior of the vesicles. This constructional role of water opens new concepts for the creation of aqueous assemblies with water-mediated functions.

Therapeutic role of recurrent ESR1-CCDC170 gene fusions in breast cancer endocrine resistance.

BACKGROUND: Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes, and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously, we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance has not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized. METHODS: The endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays. RESULTS: Our results suggested that different ESR1-CCDC170 fusions endow different levels of reduced endocrine sensitivity in vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling. Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib. CONCLUSION: ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.

Landscape analysis of adjacent gene rearrangements reveals BCL2L14-ETV6 gene fusions in more aggressive triple-negative breast cancer.

Triple-negative breast cancer (TNBC) accounts for 10 to 20% of breast cancer, with chemotherapy as its mainstay of treatment due to lack of well-defined targets, and recent genomic sequencing studies have revealed a paucity of TNBC-specific mutations. Recurrent gene fusions comprise a class of viable genetic targets in solid tumors; however, their role in breast cancer remains underappreciated due to the complexity of genomic rearrangements in this cancer. Our interrogation of the whole-genome sequencing data for 215 breast tumors catalogued 99 recurrent gene fusions, 57% of which are cryptic adjacent gene rearrangements (AGRs). The most frequent AGRs, BCL2L14-ETV6, TTC6-MIPOL1, ESR1-CCDC170, and AKAP8-BRD4, were preferentially found in the more aggressive forms of breast cancers that lack well-defined genetic targets. Among these, BCL2L14-ETV6 was exclusively detected in TNBC, and interrogation of four independent patient cohorts detected BCL2L14-ETV6 in 4.4 to 12.2% of TNBC tumors. Interestingly, these fusion-positive tumors exhibit more aggressive histopathological features, such as gross necrosis and high tumor grade. Amid TNBC subtypes, BCL2L14-ETV6 is most frequently detected in the mesenchymal entity, accounting for ∼19% of these tumors. Ectopic expression of BCL2L14-ETV6 fusions induce distinct expression changes from wild-type ETV6 and enhance cell motility and invasiveness of TNBC and benign breast epithelial cells. Furthermore, BCL2L14-ETV6 fusions prime partial epithelial-mesenchymal transition and endow resistance to paclitaxel treatment. Together, these data reveal AGRs as a class of underexplored genetic aberrations that could be pathological in breast cancer, and identify BCL2L14-ETV6 as a recurrent gene fusion in more aggressive form of TNBC tumors.