Breast Cancer Research最新文献

{"title":"PFKP deubiquitination and stabilization by USP5 activate aerobic glycolysis to promote triple-negative breast cancer progression.","authors":"Zi-Mei Peng, Xiao-Jian Han, Tao Wang, Jian-Jun Li, Chun-Xi Yang, Fang-Fang Tou, Zhen Zhang","doi":"10.1186/s13058-024-01767-z","DOIUrl":"10.1186/s13058-024-01767-z","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) remains the most challenging subtype of breast cancer and lacks definite treatment targets. Aerobic glycolysis is a hallmark of metabolic reprogramming that contributes to cancer progression. PFKP is a rate-limiting enzyme involved in aerobic glycolysis, which is overexpressed in various types of cancers. However, the underlying mechanisms and roles of the posttranslational modification of PFKP in TNBC remain unknown.</p><p><strong>Methods: </strong>To explore whether PFKP protein has a potential role in the progression of TNBC, protein levels of PFKP in TNBC and normal breast tissues were examined by CPTAC database analysis, immunohistochemistry staining (IHC), and western blotting assay. Further CCK-8 assay, colony formation assay, EDU incorporation assay, and tumor xenograft experiments were used to detect the effect of PFKP on TNBC progression. To clarify the role of the USP5-PFKP pathway in TNBC progression, ubiquitin assay, co-immunoprecipitation (Co-IP), mass spectrometry-based protein identification, western blotting assay, immunofluorescence microscopy, in vitro binding assay, and glycolysis assay were conducted.</p><p><strong>Results: </strong>Herein, we showed that PFKP protein was highly expressed in TNBC, which was associated with TNBC progression and poor prognosis of patients. In addition, we demonstrated that PFKP depletion significantly inhibited the TNBC progression in vitro and in vivo. Importantly, we identified that PFKP was a bona fide target of deubiquitinase USP5, and the USP5-mediated deubiquitination and stabilization of PFKP were essential for cancer cell aerobic glycolysis and TNBC progression. Moreover, we found a strong positive correlation between the expression of USP5 and PFKP in TNBC samples. Notably, the high expression of USP5 and PFKP was significantly correlated with poor clinical outcomes.</p><p><strong>Conclusions: </strong>Our study established the USP5-PFKP axis as an important regulatory mechanism of TNBC progression and provided a rationale for future therapeutic interventions in the treatment of TNBC.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10787506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139433006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic value of baseline neutrophil/lymphocyte ratio in HER2-positive metastatic breast cancer: exploratory analysis of data from the CLEOPATRA trial.","authors":"Nianhua Ding, Jian Pang, Xuan Liu, Xiongbin He, Wei Zhou, Haiqing Xie, Jianqi Feng, Guo Wang, Jie Tang, Jing Cao, Liying He, Yingjian He, Shouman Wang, Zhi Xiao","doi":"10.1186/s13058-023-01761-x","DOIUrl":"10.1186/s13058-023-01761-x","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to evaluate the prognostic role of the baseline neutrophil/lymphocyte ratio (NLR) in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab/pertuzumab.</p><p><strong>Experimental design: </strong>Data from 780 patients from the CLEOPATRA trial and 248 local patients were collected. Patients were divided into the low and high NLR subgroups by the NLR cutoff value. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) methods were used to control bias. Associations between the NLR and progression-free survival (PFS) and overall survival (OS) were analyzed.</p><p><strong>Results: </strong>The baseline characteristics of the subgroups were well balanced after PSM and IPTW. A low baseline NLR was associated with better PFS and OS in the trastuzumab and docetaxel (TH) group in the unadjusted, PSM and IPTW models. After IPTW, a low NLR, versus a high NLR, was associated with improved PFS (HR 1.35, 95% CI 1.07-1.70, P = 0.012) and OS (HR 1.47, 95% CI 1.12-1.94, P = 0.006) in the TH group. In patients undergoing treatment with trastuzumab and pertuzumab and docetaxel (THP), a low baseline NLR was also correlated with better PFS but not OS across the three models. After IPTW, a low NLR was associated with better PFS (HR 1.52, 95% CI 1.20-1.93, P = 0.001) than a high NLR in the THP group. Multivariate analyses showed that a low baseline NLR was a predictor for PFS and OS in the TH group and for PFS in the THP group in all three models. In the real-world setting, a low baseline NLR was a predictor of better PFS among patients treated with docetaxel plus trastuzumab without or with pertuzumab in the multivariate model (P = 0.015 and 0.008, respectively).</p><p><strong>Conclusions: </strong>A low baseline NLR is associated with better survival outcomes among HER2-positive MBC patients receiving docetaxel plus trastuzumab/pertuzumab as first-line therapy.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10785455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139425830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant.","authors":"Ines Block, Àngels Mateu-Regué, Thi Tuyet Nhu Do, Ieva Miceikaite, Daniel Sdogati, Martin J Larsen, Qin Hao, Henriette Roed Nielsen, Susanne E Boonen, Anne-Bine Skytte, Uffe Birk Jensen, Louise K Høffding, Arcangela De Nicolo, Alessandra Viel, Emma Tudini, Michael T Parsons, Thomas V O Hansen, Maria Rossing, Torben A Kruse, Amanda B Spurdle, Mads Thomassen","doi":"10.1186/s13058-023-01755-9","DOIUrl":"10.1186/s13058-023-01755-9","url":null,"abstract":"<p><strong>Background: </strong>Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype.</p><p><strong>Methods: </strong>We identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells.</p><p><strong>Results: </strong>Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability.</p><p><strong>Conclusions: </strong>This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10775606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139404926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a Notch transcriptomic signature for breast cancer.","authors":"Eike-Benjamin Braune, Felix Geist, Xiaojia Tang, Krishna Kalari, Judy Boughey, Liewei Wang, Roberto A Leon-Ferre, Antonino B D'Assoro, James N Ingle, Matthew P Goetz, Julian Kreis, Kang Wang, Theodoros Foukakis, Anita Seshire, Dirk Wienke, Urban Lendahl","doi":"10.1186/s13058-023-01757-7","DOIUrl":"10.1186/s13058-023-01757-7","url":null,"abstract":"<p><strong>Background: </strong>Dysregulated Notch signalling contributes to breast cancer development and progression, but validated tools to measure the level of Notch signalling in breast cancer subtypes and in response to systemic therapy are largely lacking. A transcriptomic signature of Notch signalling would be warranted, for example to monitor the effects of future Notch-targeting therapies and to learn whether altered Notch signalling is an off-target effect of current breast cancer therapies. In this report, we have established such a classifier.</p><p><strong>Methods: </strong>To generate the signature, we first identified Notch-regulated genes from six basal-like breast cancer cell lines subjected to elevated or reduced Notch signalling by culturing on immobilized Notch ligand Jagged1 or blockade of Notch by γ-secretase inhibitors, respectively. From this cadre of Notch-regulated genes, we developed candidate transcriptomic signatures that were trained on a breast cancer patient dataset (the TCGA-BRCA cohort) and a broader breast cancer cell line cohort and sought to validate in independent datasets.</p><p><strong>Results: </strong>An optimal 20-gene transcriptomic signature was selected. We validated the signature on two independent patient datasets (METABRIC and Oslo2), and it showed an improved coherence score and tumour specificity compared with previously published signatures. Furthermore, the signature score was particularly high for basal-like breast cancer, indicating an enhanced level of Notch signalling in this subtype. The signature score was increased after neoadjuvant treatment in the PROMIX and BEAUTY patient cohorts, and a lower signature score generally correlated with better clinical outcome.</p><p><strong>Conclusions: </strong>The 20-gene transcriptional signature will be a valuable tool to evaluate the response of future Notch-targeting therapies for breast cancer, to learn about potential effects on Notch signalling from conventional breast cancer therapies and to better stratify patients for therapy considerations.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10765899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139089077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Key regulator PNPLA8 drives phospholipid reprogramming induced proliferation and migration in triple-negative breast cancer.","authors":"Zheqiong Tan, Pragney Deme, Keerti Boyapati, Britt S R Claes, Annet A M Duivenvoorden, Ron M A Heeren, Caitlin M Tressler, Norman James Haughey, Kristine Glunde","doi":"10.1186/s13058-023-01742-0","DOIUrl":"10.1186/s13058-023-01742-0","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and leads to the poorest patient outcomes despite surgery and chemotherapy treatment. Exploring new molecular mechanisms of TNBC that could lead to the development of novel molecular targets are critically important for improving therapeutic options for treating TNBC.</p><p><strong>Methods: </strong>We sought to identify novel therapeutic targets in TNBC by combining genomic and functional studies with lipidomic analysis, which included mechanistic studies to elucidate the pathways that tie lipid profile to critical cancer cell properties. Our studies were performed in a large panel of human breast cancer cell lines and patient samples.</p><p><strong>Results: </strong>Comprehensive lipid profiling revealed that phospholipid metabolism is reprogrammed in TNBC cells. We discovered that patatin-like phospholipase domain-containing lipase 8 (PNPLA8) is overexpressed in TNBC cell lines and tissues from breast cancer patients. Silencing of PNPLA8 disrupted phospholipid metabolic reprogramming in TNBC, particularly affecting the levels of phosphatidylglycerol (PG), phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and glycerophosphocholine (GPC). We showed that PNPLA8 is essential in regulating cell viability, migration and antioxidation in TNBC cells and promoted arachidonic acid and eicosanoid production, which in turn activated PI3K/Akt/Gsk3β and MAPK signaling.</p><p><strong>Conclusions: </strong>Our study highlights PNPLA8 as key regulator of phospholipid metabolic reprogramming and malignant phenotypes in TNBC, which could be further developed as a novel molecular treatment target.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10683240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138452895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and evaluation of a method to assess breast cancer risk using a longitudinal history of mammographic density: a cohort study.","authors":"Emma C Atakpa, Diana S M Buist, Erin J Aiello Bowles, Jack Cuzick, Adam R Brentnall","doi":"10.1186/s13058-023-01744-y","DOIUrl":"10.1186/s13058-023-01744-y","url":null,"abstract":"<p><strong>Background: </strong>Women with dense breasts have an increased risk of breast cancer. However, breast density is measured with variability, which may reduce the reliability and accuracy of its association with breast cancer risk. This is particularly relevant when visually assessing breast density due to variation in inter- and intra-reader assessments. To address this issue, we developed a longitudinal breast density measure which uses an individual woman's entire history of mammographic density, and we evaluated its association with breast cancer risk as well as its predictive ability.</p><p><strong>Methods: </strong>In total, 132,439 women, aged 40-73 yr, who were enrolled in Kaiser Permanente Washington and had multiple screening mammograms taken between 1996 and 2013 were followed up for invasive breast cancer through 2014. Breast Imaging Reporting and Data System (BI-RADS) density was assessed at each screen. Continuous and derived categorical longitudinal density measures were developed using a linear mixed model that allowed for longitudinal density to be updated at each screen. Predictive ability was assessed using (1) age and body mass index-adjusted hazard ratios (HR) for breast density (time-varying covariate), (2) likelihood-ratio statistics (ΔLR-χ²) and (3) concordance indices.</p><p><strong>Results: </strong>In total, 2704 invasive breast cancers were diagnosed during follow-up (median = 5.2 yr; median mammograms per woman = 3). When compared with an age- and body mass index-only model, the gain in statistical information provided by the continuous longitudinal density measure was 23% greater than that provided by BI-RADS density (follow-up after baseline mammogram: ΔLR-χ² = 379.6 (degrees of freedom (df) = 2) vs. 307.7 (df = 3)), which increased to 35% (ΔLR-χ² = 251.2 vs. 186.7) for follow-up after three mammograms (n = 76,313, 2169 cancers). There was a sixfold difference in observed risk between densest and fattiest eight-category longitudinal density (HR = 6.3, 95% CI 4.7-8.7), versus a fourfold difference with BI-RADS density (HR = 4.3, 95% CI 3.4-5.5). Discriminatory accuracy was marginally greater for longitudinal versus BI-RADS density (c-index = 0.64 vs. 0.63, mean difference = 0.008, 95% CI 0.003-0.012).</p><p><strong>Conclusions: </strong>Estimating mammographic density using a woman's history of breast density is likely to be more reliable than using the most recent observation only, which may lead to more reliable and accurate estimates of individual breast cancer risk. Longitudinal breast density has the potential to improve personal breast cancer risk estimation in women attending mammography screening.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2023-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10668455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138435278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histologic tumor type as a determinant of survival in hormone receptor-positive, HER2-negative, pT1-3 invasive ductal and lobular breast cancer.","authors":"Menekse Göker, Hannelore Denys, An Hendrix, Olivier De Wever, Koen Van de Vijver, Geert Braems","doi":"10.1186/s13058-023-01745-x","DOIUrl":"10.1186/s13058-023-01745-x","url":null,"abstract":"<p><strong>Purpose: </strong>The aim of the study was to compare the difference in survival between invasive ductal (IDC) and lobular carcinoma (ILC).</p><p><strong>Methods: </strong>Data of patients (n = 1843) with a hormone receptor-positive, HER2-negative, pT1-3 IDC or ILC cancer without distant metastasis, treated at the Ghent University Hospital over the time period 2001-2015, were analyzed.</p><p><strong>Results: </strong>ILC represented 13.9% of the tumors, had a higher percentage of pT3 and pN3 stages than IDC, lymphovascular space invasion (LVSI) was less present and Ki-67 was mostly low. 73.9% of ILCs were grade 2, whereas IDC had more grade 1 and grade 3 tumors. Kaplan-Meier curves and log-rank testing showed a significant worse DFS for ILC with pN ≥ 1 than for their IDC counterpart. In a multivariable Cox regression analysis the histologic tumor type, ductal or lobular, was a determinant of DFS over 120 months (IDC as reference; hazard ratio for ILC 1.77, 95% CI 1.08-2.90) just as the ER Allred score (hazard ratio 0.84, 95% CI 0.78-0.91), LVSI (hazard ratio 1.75, 95% CI 1.12-2.74) and pN3 (hazard ratio 2.29, 95% CI 1.03-5.09). Determinants of OS over ten years were age (hazard ratio 1.05, 95% CI 1.02-1.07), LVSI (hazard ratio 3.62, 95% CI 1.92-6.82) and the ER Allred score (hazard ratio 0.80, 95% CI 0.73-0.89).</p><p><strong>Conclusion: </strong>The histologic tumor type, ductal or lobular, determines DFS in hormone receptor-positive, HER2-negative, pT1-3 breast cancer besides the ER Allred score, LVSI and pN3.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138296359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative whole-genome and transcriptome analysis of HER2-amplified metastatic breast cancer.","authors":"Noortje Verschoor, Marcel Smid, Agnes Jager, Stefan Sleijfer, Saskia M Wilting, John W M Martens","doi":"10.1186/s13058-023-01743-z","DOIUrl":"10.1186/s13058-023-01743-z","url":null,"abstract":"<p><strong>Background: </strong>In breast cancer, the advent of anti-HER2 therapies has made HER2+ tumors a highly relevant subgroup. However, the exact characteristics which prohibit clinical response to anti-HER2 therapies and drive disease progression are not yet fully known. Integrative whole-genome and transcriptomic sequencing data from both primary and metastatic HER2-positive breast cancer will enhance our understanding of underlying biological processes.</p><p><strong>Methods: </strong>Here, we used WGS and RNA sequencing data of 700 metastatic breast tumors, of which 68 being HER2+, to search for specific genomic features of HER2+ disease and therapy resistance. Furthermore, we integrated results with transcriptomic data to associate tumors exhibiting a HER2+-specific gene expression profile with ERBB2 mutation status, prior therapy and relevant gene expression signatures.</p><p><strong>Results: </strong>Overall genomic profiles of primary and metastatic HER2+ breast cancers were similar, and no specific acquired genomics traits connected to prior anti-HER2 treatment were observed. However, specific genomic features were predictive of progression-free survival on post-biopsy anti-HER2 treatment. Furthermore, a HER2-driven expression profile grouped HER2-amplified tumors with ERBB2-mutated cases and cases without HER2 alterations. The latter were reported as ER positive in primary disease, but the metastatic biopsy showed low ESR1 expression and upregulation of the MAPK pathway, suggesting transformation to ER independence.</p><p><strong>Conclusions: </strong>In summary, although the quantity of variants increased throughout HER2-positive breast cancer progression, the genomic composition remained largely consistent, thus yielding no new major processes beside those already operational in primary disease. Our results suggest that integrated genomic and transcriptomic analyses may be key in establishing therapeutic options.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10648326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134650324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The BET degrader ZBC260 suppresses stemness and tumorigenesis and promotes differentiation in triple-negative breast cancer by disrupting inflammatory signaling.","authors":"Deeksha Sharma, Cody G Hager, Li Shang, Lam Tran, Yongyou Zhu, Aihui Ma, Brian Magnuson, Matthew W Lesko, Max S Wicha, Monika L Burness","doi":"10.1186/s13058-023-01715-3","DOIUrl":"10.1186/s13058-023-01715-3","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer stem cells (BCSCs) are resistant to standard therapies, facilitate tumor dissemination, and contribute to relapse and progression. Super-enhancers are regulators of stemness, and BET proteins, which are critical for super-enhancer function, are a potential therapeutic target. Here, we investigated the effects of BET proteins on the regulation of breast cancer stemness using the pan-BET degrader ZBC260.</p><p><strong>Methods: </strong>We evaluated the effect of ZBC260 on CSCs in TNBC cell lines. We assessed the effect of ZBC260 on cellular viability and tumor growth and measured its effects on cancer stemness. We used RNA sequencing and stemness index to determine the global transcriptomic changes in CSCs and bulk cells and further validated our findings by qPCR, western blot, and ELISA.</p><p><strong>Results: </strong>ZBC260 potently inhibited TNBC growth both in vitro and in vivo. ZBC260 reduced stemness as measured by cell surface marker expression, ALDH activity, tumorsphere number, and stemness index while increasing differentiated cells. GSEA analysis indicated preferential downregulation of stemness-associated and inflammatory genes by ZBC260 in ALDH⁺ CSCs.</p><p><strong>Conclusions: </strong>The BET degrader ZBC260 is an efficient degrader of BET proteins that suppresses tumor progression and decreases CSCs through the downregulation of inflammatory genes and pathways. Our findings support the further development of BET degraders alone and in combination with other therapeutics as CSC targeting agents.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10648675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134650325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formation of an invasion-permissive matrix requires TGFβ/SNAIL1-regulated alternative splicing of fibronectin.","authors":"Héctor Franco-Valls, Elsa Tusquets-Uxó, Laura Sala, Maria Val, Raúl Peña, Alessandra Iaconcig, Álvaro Villarino, Martín Jiménez-Arriola, Pere Massó, Juan L Trincado, Eduardo Eyras, Andrés F Muro, Jorge Otero, Antonio García de Herreros, Josep Baulida","doi":"10.1186/s13058-023-01736-y","DOIUrl":"10.1186/s13058-023-01736-y","url":null,"abstract":"<p><strong>Background: </strong>As in most solid cancers, the emergence of cells with oncogenic mutations in the mammary epithelium alters the tissue homeostasis. Some soluble factors, such as TGFβ, potently modify the behavior of healthy stromal cells. A subpopulation of cancer-associated fibroblasts expressing a TGFβ target, the SNAIL1 transcription factor, display myofibroblastic abilities that rearrange the stromal architecture. Breast tumors with the presence of SNAIL1 in the stromal compartment, and with aligned extracellular fiber, are associated with poor survival prognoses.</p><p><strong>Methods: </strong>We used deep RNA sequencing and biochemical techniques to study alternative splicing and human tumor databases to test for associations (correlation t-test) between SNAIL1 and fibronectin isoforms. Three-dimensional extracellular matrices generated from fibroblasts were used to study the mechanical properties and actions of the extracellular matrices on tumor cell and fibroblast behaviors. A metastatic mouse model of breast cancer was used to test the action of fibronectin isoforms on lung metastasis.</p><p><strong>Results: </strong>In silico studies showed that SNAIL1 correlates with the expression of the extra domain A (EDA)-containing (EDA+) fibronectin in advanced human breast cancer and other types of epithelial cancers. In TGFβ-activated fibroblasts, alternative splicing of fibronectin as well as of 500 other genes was modified by eliminating SNAIL1. Biochemical analyses demonstrated that SNAIL1 favors the inclusion of the EDA exon by modulating the activity of the SRSF1 splicing factor. Similar to Snai1 knockout fibroblasts, EDA- fibronectin fibroblasts produce an extracellular matrix  that does not sustain TGFβ-induced fiber organization, rigidity, fibroblast activation, or tumor cell invasion. The presence of EDA+ fibronectin changes the action of metalloproteinases on fibronectin fibers. Critically, in an mouse orthotopic breast cancer model, the absence of the fibronectin EDA domain completely prevents lung metastasis.</p><p><strong>Conclusions: </strong>Our results support the requirement of EDA+ fibronectin in the generation of a metastasis permissive stromal architecture in breast cancers and its molecular control by SNAIL1. From a pharmacological point of view, specifically blocking EDA+ fibronectin deposition could be included in studies to reduce the formation of a pro-metastatic environment.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10647173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"107592554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}