Breast Cancer Research : BCR最新文献

{"title":"Risks of second non-breast primaries following breast cancer in women: a systematic review and meta-analysis.","authors":"Isaac Allen, Hend Hassan, Eleni Sofianopoulou, Diana Eccles, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C Antoniou","doi":"10.1186/s13058-023-01610-x","DOIUrl":"10.1186/s13058-023-01610-x","url":null,"abstract":"<p><strong>Background: </strong>Second primary cancer incidence is rising among breast cancer survivors. We examined the risks of non-breast second primaries, in combination and at specific cancer sites, through a systematic review and meta-analysis.</p><p><strong>Methods: </strong>We conducted a systematic search of PubMed, Embase, and Web of Science, seeking studies published by March 2022. We included studies that reported standardized incidence ratios (SIRs), with associated standard errors, assessing the combined risk of second non-breast primaries following breast cancer. We performed meta-analyses of combined second primary risks, stratifying by age, follow-up duration, and geographic region. We also assessed second primary risks at several specific sites, stratifying by age. The inverse variance method with DerSimonian-Laird estimators was used in all meta-analyses, assuming a random-effects model. Associated biases and study quality were evaluated using the Newcastle-Ottawa scale.</p><p><strong>Results: </strong>One prospective and twenty-seven retrospective cohort studies were identified. SIRs for second non-breast primaries combined ranged from 0.84 to 1.84. The summary SIR estimate was 1.24 (95% CI 1.14-1.36, I²: 99%). This varied by age: the estimate was 1.59 (95% CI 1.36-1.85) when breast cancer was diagnosed before age 50, which was significantly higher than in women first diagnosed at 50 or over (SIR: 1.13, 95% CI 1.01-1.36, p for difference: < 0.001). SPC risks were also significantly higher when based on Asian, rather than European, registries (Asia-SIR: 1.47, 95% CI 1.29-1.67. Europe-SIR: 1.16, 95% CI 1.04-1.28). There were significantly increased risks of second thyroid (SIR: 1.89, 95% CI 1.49-2.38), corpus uteri (SIR: 1.84, 95% CI 1.53-2.23), ovary (SIR: 1.53, 95% CI 1.35-1.73), kidney (SIR: 1.43, 95% CI 1.17-1.73), oesophagus (SIR: 1.39, 95% CI 1.26-1.55), skin (melanoma) (SIR: 1.34, 95% CI 1.18-1.52), blood (leukaemia) (SIR: 1.30, 95% CI 1.17-1.45), lung (SIR: 1.25, 95% CI 1.03-1.51), stomach (SIR: 1.23, 95% CI 1.12-1.36) and bladder (SIR: 1.15, 95% CI 1.05-1.26) primaries.</p><p><strong>Conclusions: </strong>Breast cancer survivors are at significantly increased risk of second primaries at many sites. Risks are higher for those diagnosed with breast cancer before age 50 and in Asian breast cancer survivors compared to European breast cancer survivors. This study is limited by a lack of data on potentially confounding variables. The conclusions may inform clinical management decisions following breast cancer, although specific clinical recommendations lie outside the scope of this review.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9912682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10281121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL3 depletion contributes to tumour progression and drug resistance via N6 methyladenosine-dependent mechanism in HR+HER2-breast cancer.","authors":"Dengjie Ouyang,&nbsp;Tao Hong,&nbsp;Mengdie Fu,&nbsp;Yitong Li,&nbsp;Liyun Zeng,&nbsp;Qitong Chen,&nbsp;Hongye He,&nbsp;Ying Wen,&nbsp;Yan Cheng,&nbsp;Meirong Zhou,&nbsp;Qiongyan Zou,&nbsp;Wenjun Yi","doi":"10.1186/s13058-022-01598-w","DOIUrl":"https://doi.org/10.1186/s13058-022-01598-w","url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy is an important strategy for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+HER2-) breast cancer (BC), but this subtype has a low response rate to chemotherapy. Growing evidence indicates that N⁶-methyladenosine (m⁶A) is the most common RNA modification in eukaryotic cells and that methyltransferase-like 3 (METTL3) participates in tumour progression in several cancer types. Therefore, exploring the function of METTL3 in HR+HER2- BC initiation and development is still important.</p><p><strong>Methods: </strong>mRNA and protein expression levels were analysed by quantitative real-time polymerase chain reaction and western blotting, respectively. Cell proliferation was detected by CCK-8 and colony formation assays. Cell cycle progression was assessed by flow cytometry. Cell migration and invasion were analysed by wound healing assays and transwell assays, respectively, and apoptosis was analysed by TUNEL assays. Finally, m⁶A modification was analysed by methylated RNA immunoprecipitation.</p><p><strong>Results: </strong>Chemotherapy-induced downregulation of the m⁶A modification is regulated by METTL3 depletion in HR+HER2- BC. METTL3 knockdown in MCF-7/T47D cells decreased the drug sensitivity of HR+HER2- BC cells by promoting tumour proliferation and migration and inhibiting apoptosis. Mechanistically, CDKN1A is a downstream target of METTL3 that activates the AKT pathway and promotes epithelial-mesenchymal transformation (EMT). Moreover, a decrease in BAX expression was observed when m⁶A modification was inhibited with METTL3 knockdown, and apoptosis was inhibited by the reduction of caspase-3/-9/-8.</p><p><strong>Conclusion: </strong>METTL3 depletion promotes the proliferation and migration and decreases the drug sensitivity of HR+HER2- BC via regulation of the CDKN1A/EMT and m⁶A-BAX/caspase-9/-3/-8 signalling pathways, which suggests METTL3 played a tumour-suppressor role and it could be a potential biomarker for predicting the prognosis of patients with HR+HER2- BC.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9921123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10788095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation and comparison of different breast cancer prognosis scores based on gene expression data.","authors":"Avirup Chowdhury, Paul D Pharoah, Oscar M Rueda","doi":"10.1186/s13058-023-01612-9","DOIUrl":"10.1186/s13058-023-01612-9","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer is one of the three most common cancers worldwide and is the most common malignancy in women. Treatment approaches for breast cancer are diverse and varied. Clinicians must balance risks and benefits when deciding treatments, and models have been developed to support this decision-making. Genomic risk scores (GRSs) may offer greater clinical value than standard clinicopathological models, but there is limited evidence as to whether these models perform better than the current clinical standard of care.</p><p><strong>Methods: </strong>PREDICT and GRSs were adapted using data from the original papers. Univariable Cox proportional hazards models were produced with breast cancer-specific survival (BCSS) as the outcome. Independent predictors of BCSS were used to build multivariable models with PREDICT. Signatures which provided independent prognostic information in multivariable models were incorporated into the PREDICT algorithm and assessed for calibration, discrimination and reclassification.</p><p><strong>Results: </strong>EndoPredict, MammaPrint and Prosigna demonstrated prognostic power independent of PREDICT in multivariable models for ER-positive patients; no score predicted BCSS in ER-negative patients. Incorporating these models into PREDICT had only a modest impact upon calibration (with absolute improvements of 0.2-0.8%), discrimination (with no statistically significant c-index improvements) and reclassification (with 4-10% of patients being reclassified).</p><p><strong>Conclusion: </strong>Addition of GRSs to PREDICT had limited impact on model fit or treatment received. This analysis does not support widespread adoption of current GRSs based on our implementations of commercial products.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9906838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10812895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Changes in the tumor oxygenation but not in the tumor volume and tumor vascularization reflect early response of breast cancer to neoadjuvant chemotherapy.","authors":"Mikhail V Pavlov,&nbsp;Anna P Bavrina,&nbsp;Vladimir I Plekhanov,&nbsp;German Yu Golubyatnikov,&nbsp;Anna G Orlova,&nbsp;Pavel V Subochev,&nbsp;Diana A Davydova,&nbsp;Ilya V Turchin,&nbsp;Anna V Maslennikova","doi":"10.1186/s13058-023-01614-7","DOIUrl":"https://doi.org/10.1186/s13058-023-01614-7","url":null,"abstract":"","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9903525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10806411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: A prospective case-cohort analysis of plasma metabolites and breast cancer risk.","authors":"Victoria L Stevens,&nbsp;Brian D Carter,&nbsp;Eric J Jacobs,&nbsp;Marjorie L McCullough,&nbsp;Lauren R Teras,&nbsp;Ying Wang","doi":"10.1186/s13058-023-01613-8","DOIUrl":"https://doi.org/10.1186/s13058-023-01613-8","url":null,"abstract":"","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9893579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10856339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Multimorbidity and overall survival among women with breast cancer: results from the South African Breast Cancer and HIV Outcomes Study.","authors":"Oluwatosin A Ayeni, Maureen Jofe, Witness Mapanga, Wenlong Carl Chen, Daniel S O'Neil, Boitumelo Phakathi, Sarah Nietz, Ines Buccimazza, Sharon Čačala, Laura W Stopforth, Judith S Jacobson, Katherine D Crew, Alfred I Neugut, Duvern Ramiah, Paul Ruf, Herbert Cubasch, Tobias Chirwa, Valerie McCormack, Lisa K Micklesfeld, Shane A Norris","doi":"10.1186/s13058-023-01611-w","DOIUrl":"10.1186/s13058-023-01611-w","url":null,"abstract":"","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9890739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10632736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of hormone receptors is associated with specific immunological profiles of the breast cancer microenvironment.","authors":"Toru Hanamura,&nbsp;Shigehisa Kitano,&nbsp;Hiroshi Kagamu,&nbsp;Makiko Yamashita,&nbsp;Mayako Terao,&nbsp;Takuho Okamura,&nbsp;Nobue Kumaki,&nbsp;Katsuto Hozumi,&nbsp;Takayuki Iwamoto,&nbsp;Chikako Honda,&nbsp;Sasagu Kurozumi,&nbsp;Naoki Niikura","doi":"10.1186/s13058-023-01606-7","DOIUrl":"https://doi.org/10.1186/s13058-023-01606-7","url":null,"abstract":"<p><strong>Background: </strong>Elucidating the unique immunoregulatory mechanisms in breast cancer microenvironment may help develop new therapeutic strategies. Some studies have suggested that hormone receptors also have immune regulatory functions, but their mechanisms are not fully understood. In this study, we have comprehensively analyzed the relationship between the expressions of estrogen (ER), progesterone (PgR), and androgen receptors (AR), and the immunological profile in breast cancer.</p><p><strong>Methods: </strong>Using publicly available gene expression profile datasets, METABRIC and SCAN-B, the associations between the expressions of hormone receptors and the immune cell compositions in breast cancer tissue, estimated by CIBERSORTx algorithm, were analyzed. We histologically evaluated tumor-infiltrating lymphocytes (hTIL), PD-L1 (hPD-L1) expression, and the infiltration of 11 types of immune cells by flow cytometry (FCM) for 45 breast cancer tissue samples. The relationships between them and the expressions of ER, PgR, and AR of tumor tissues, evaluated immunohistochemically, were analyzed.</p><p><strong>Results: </strong>Expressions of ESR1, PGR, and AR were negatively correlated with overall immune composition. Expressions of ER and AR, but not that of PgR, were inversely associated with hTIL and hPD-L1 expression. FCM analysis showed that the expressions of ER and AR, but not that of PgR, were associated with decreased total leukocyte infiltration. Both CIBERSORTx and FCM analysis showed that ER expression was associated with reduced infiltration of macrophages and CD4+ T cells and that of AR with reduced macrophage infiltration.</p><p><strong>Conclusion: </strong>Hormone receptor expression correlates with specific immunological profiles in the breast cancer microenvironment both at the gene and protein expression levels.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9887885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9136992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in the tumor oxygenation but not in the tumor volume and tumor vascularization reflect early response of breast cancer to neoadjuvant chemotherapy.","authors":"Mikhail V Pavlov,&nbsp;Anna P Bavrina,&nbsp;Vladimir I Plekhanov,&nbsp;German Yu Golubyatnikov,&nbsp;Anna G Orlova,&nbsp;Pavel V Subochev,&nbsp;Diana A Davydova,&nbsp;Ilya V Turchin,&nbsp;Anna V Maslennikova","doi":"10.1186/s13058-023-01607-6","DOIUrl":"https://doi.org/10.1186/s13058-023-01607-6","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer neoadjuvant chemotherapy (NACT) allows for assessing tumor sensitivity to systemic treatment, planning adjuvant treatment and follow-up. However, a sufficiently large number of patients fail to achieve the desired level of pathological tumor response while optimal early response assessment methods have not been established now. In our study, we simultaneously assessed the early chemotherapy-induced changes in the tumor volume by ultrasound (US), the tumor oxygenation by diffuse optical spectroscopy imaging (DOSI), and the state of the tumor vascular bed by Doppler US to elaborate the predictive criteria of breast tumor response to treatment.</p><p><strong>Methods: </strong>A total of 133 patients with a confirmed diagnosis of invasive breast cancer stage II to III admitted to NACT following definitive breast surgery were enrolled, of those 103 were included in the final analysis. Tumor oxygenation by DOSI, tumor volume by US, and tumor vascularization by Doppler US were determined before the first and second cycle of NACT. After NACT completion, patients underwent surgery followed by pathological examination and assessment of the pathological tumor response. On the basis of these, data regression predictive models were created.</p><p><strong>Results: </strong>We observed changes in all three parameters 3 weeks after the start of the treatment. However, a high predictive potential for early assessment of tumor sensitivity to NACT demonstrated only the level of oxygenation, ΔStO₂, (ρ = 0.802, p ≤ 0.01). The regression model predicts the tumor response with a high probability of a correct conclusion (89.3%). The \"Tumor volume\" model and the \"Vascularization index\" model did not accurately predict the absence of a pathological tumor response to treatment (60.9% and 58.7%, respectively), while predicting a positive response to treatment was relatively better (78.9% and 75.4%, respectively).</p><p><strong>Conclusions: </strong>Diffuse optical spectroscopy imaging appeared to be a robust tool for early predicting breast cancer response to chemotherapy. It may help identify patients who need additional molecular genetic study of the tumor in order to find the source of resistance to treatment, as well as to correct the treatment regimen.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9887770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9178753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic alterations underlying metaplasia into specific metaplastic components in metaplastic breast carcinoma.","authors":"Huang-Chun Lien,&nbsp;Chia-Lang Hsu,&nbsp;Yen-Shen Lu,&nbsp;Tom Wei-Wu Chen,&nbsp;I-Chun Chen,&nbsp;Yu-Chia Li,&nbsp;Chiun-Sheng Huang,&nbsp;Ann-Lii Cheng,&nbsp;Ching-Hung Lin","doi":"10.1186/s13058-023-01608-5","DOIUrl":"https://doi.org/10.1186/s13058-023-01608-5","url":null,"abstract":"<p><strong>Background: </strong>Metaplastic breast carcinoma (MpBC) typically consists of carcinoma of no special type (NST) with various metaplastic components. Although previous transcriptomic and proteomic studies have reported subtype-related heterogeneity, the intracase transcriptomic alterations between metaplastic components and paired NST components, which are critical for understanding the pathogenesis underlying the metaplastic processes, remain unclear.</p><p><strong>Methods: </strong>Fifty-nine NST components and paired metaplastic components (spindle carcinomatous [SPS], matrix-producing, rhabdoid [RHA], and squamous carcinomatous [SQC] components) were microdissected from specimens obtained from 27 patients with MpBC for gene expression profiling using the NanoString Breast Cancer 360 Panel on a NanoString nCounter FLEX platform. BC360-defined signatures were scored using nSolver software.</p><p><strong>Results: </strong>Hierarchical clustering and principal component analysis revealed a heterogeneous gene expression profile (GEP) corresponding to the NST components, but the GEP of metaplastic components exhibited subtype dependence. Compared with the paired NST components, the SPS components demonstrated the upregulation of genes related to stem cells and epithelial-mesenchymal transition and displayed enrichment in claudin-low and macrophage signatures. Despite certain overlaps in the enriched functions and signatures between the RHA and SPS components, the specific differentially expressed genes differed. We observed the RHA-specific upregulation of genes associated with vascular endothelial growth factor signaling. The chondroid matrix-producing components demonstrated the upregulation of hypoxia-related genes and the downregulation of the immune-related MHC2 signature and the TIGIT gene. In the SQC components, TGF-β and genes associated with cell adhesion were upregulated. The differentially expressed genes among metaplastic components in the 22 MpBC cases with one or predominantly one metaplastic component clustered paired NST samples into clusters with correlation with their associated metaplastic types. These genes could be used to separate the 31 metaplastic components according to respective metaplastic types with an accuracy of 74.2%, suggesting that intrinsic signatures of NST may determine paired metaplastic type. Finally, the EMT activity and stem cell traits in the NST components were correlated with specimens displaying lymph node metastasis.</p><p><strong>Conclusions: </strong>We presented the distinct transcriptomic alterations underlying metaplasia into specific metaplastic components in MpBCs, which contributes to the understanding of the pathogenesis underlying morphologically distinct metaplasia in MpBCs.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9883935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10800250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor necroptosis-mediated shedding of cell surface proteins promotes metastasis of breast cancer by suppressing anti-tumor immunity.","authors":"Zhaoshan Liu,&nbsp;Swati Choksi,&nbsp;Hyung-Joon Kwon,&nbsp;Delong Jiao,&nbsp;Chengyu Liu,&nbsp;Zheng-Gang Liu","doi":"10.1186/s13058-023-01604-9","DOIUrl":"https://doi.org/10.1186/s13058-023-01604-9","url":null,"abstract":"<p><p>Necroptosis is a form of regulated necrosis and is executed by MLKL when MLKL is engaged in triggering the rupture of cell plasma membrane. MLKL activation also leads to the protease, ADAMs-mediated ectodomain shedding of cell surface proteins of necroptotic cells. Tumor necroptosis often happens in advanced solid tumors, and blocking necroptosis by MLKL deletion in breast cancer dramatically reduces tumor metastasis. It has been suggested that tumor necroptosis affects tumor progression through modulating the tumor microenvironment. However, the exact mechanism by which tumor necroptosis promotes tumor metastasis remains elusive. Here, we report that the ectodomain shedding of cell surface proteins of necroptotic cells is critical for the promoting effect of tumor necroptosis in tumor metastasis through inhibiting the anti-tumor activity of T cells. We found that blocking tumor necroptosis by MLKL deletion led to the dramatic reduction of tumor metastasis and significantly elevated anti-tumor activity of tumor-infiltrating and peripheral blood T cells. Importantly, the increased anti-tumor activity of T cells is a key cause for the reduced metastasis as the depletion of CD8+ T cells completely restored the level of metastasis in the Mlkl KO mice. Interestingly, the levels of some soluble cell surface proteins including sE-cadherin that are known to promote metastasis are also dramatically reduced in MLKL null tumors/mice. Administration of ADAMs pan inhibitor reduces the levels of soluble cell surface proteins in WT tumors/mice and leads to the dramatic decrease in metastasis. Finally, we showed the sE-cadherin/KLRG1 inhibitory receptor is the major pathway for necroptosis-mediated suppression of the anti-tumor activity of T cells and the promotion of metastasis. Hence, our study reveals a novel mechanism of tumor necroptosis-mediated promotion of metastasis and suggests that tumor necroptosis and necroptosis-activated ADAMs are potential targets for controlling metastasis.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9881343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10798965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}