Breast Cancer Research最新文献

{"title":"Divergent paths of mammary gland involution: unveiling the cellular dynamics in abruptly and gradually involuted mouse models.","authors":"Sarmila Majumder, Sanjay Mishra, Neelam Shinde, Maria C Cuitino, Morgan Bauer, Dinesh Ahirwar, Mustafa M Basree, Vijaya Bharti, Kate Ormiston, Resham Mawalkar, Sara Alsammerai, Gautam Sarathy, Anna E Vilgelm, Xiaoli Zhang, Ramesh K Ganju, Bhuvaneswari Ramaswamy","doi":"10.1186/s13058-024-01933-3","DOIUrl":"10.1186/s13058-024-01933-3","url":null,"abstract":"<p><strong>Background: </strong>Epidemiological studies associate an increase in breast cancer risk, particularly triple-negative breast cancer (TNBC), with lack of breastfeeding. This is more prevalent in African American women, with significantly lower rate of breastfeeding compared to Caucasian women. Prolonged breastfeeding leads to gradual involution (GI), whereas short-term or lack of breastfeeding leads to abrupt involution (AI) of the breast. Our previous study utilizing a murine model demonstrated precancerous changes, specifically hyperplasia, a non-obligate precursor of breast cancer in the mammary glands of AI mice. Here we investigated mechanisms during early events of AI that prompts precancerous changes in mouse mammary glands.</p><p><strong>Methods: </strong>Uniparous FVB/N mice were randomized to AI and GI on postpartum day 7 when all pups were removed from AI dams. GI dams were allowed to nurse the pups till day 31. Cell death kinetics and gene expression were assessed by TUNEL assay and qPCR respectively. Immune cell changes were investigated by flow cytometry, cytokine array and multiplex immunofluorescence. 3D-organoid cultures were used for in vitro assay of luminal progenitor cells.</p><p><strong>Results: </strong>AI results in rapid cell death, DNA repair response, and immunosuppressive myeloid cells infiltration, leading to a chronically inflamed microenvironment. GI elicits a more controlled immune response and extended cell death. At the peak of cell death, AI glands harbored more immunosuppressive myeloid-derived suppressor cells (MDSCs) and CD206 + M2-like macrophages, known to promote oncogenic events, compared to GI glands. AI glands exhibit an enrichment of CCL9-producing MDSCs and CD206 + M2-like macrophages that promote expansion of ELF5 + /ERα- luminal cells, both in vitro and in vivo. Multiplex imaging of AI glands demonstrated an increase in ELF5 + /WNT5a + luminal cells alongside a reduction in the ELF5 + /ERα + population when involution appeared histologically complete. A significantly higher number of CD206 + cells in post involution AI gland attests to a chronically inflamed state induced by AI.</p><p><strong>Conclusions: </strong>Our findings reveal significant disparities between AI and GI gland dynamics at the early phase of involution. CCL9, secreted by immune cells at the peak of cell death promotes expansion of Elf5 + /ERα- luminal progenitor cells, the putative precursors of TNBC connecting early events of AI with increased breast cancer risk.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"1"},"PeriodicalIF":7.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928451","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":"Patient-derived response estimates from zero-passage organoids of luminal breast cancer.","authors":"Róża K Przanowska, Najwa Labban, Piotr Przanowski, Russell B Hawes, Kristen A Atkins, Shayna L Showalter, Kevin A Janes","doi":"10.1186/s13058-024-01931-5","DOIUrl":"10.1186/s13058-024-01931-5","url":null,"abstract":"<p><strong>Background: </strong>Primary luminal breast cancer cells lose their identity rapidly in standard tissue culture, which is problematic for testing hormone interventions and molecular pathways specific to the luminal subtype. Breast cancer organoids are thought to retain tumor characteristics better, but long-term viability of luminal-subtype cases is a persistent challenge. Our goal was to adapt short-term organoids of luminal breast cancer for parallel testing of genetic and pharmacologic perturbations.</p><p><strong>Methods: </strong>We freshly isolated patient-derived cells from luminal tumor scrapes, miniaturized the organoid format into 5 µl replicates for increased throughput, and set an endpoint of 14 days to minimize drift. Therapeutic hormone targeting was mimicked in these \"zero-passage\" organoids by withdrawing β-estradiol and adding 4-hydroxytamoxifen. We also examined sulforaphane as an electrophilic stress and commercial nutraceutical with reported anti-cancer properties. Downstream mechanisms were tested genetically by lentiviral transduction of two complementary sgRNAs and Cas9 stabilization for the first week of organoid culture. Transcriptional changes were measured by RT-qPCR or RNA sequencing (RNA-seq), and organoid phenotypes were quantified by serial brightfield imaging, digital image segmentation, and regression modeling of volumetric growth rates.</p><p><strong>Results: </strong>We achieved > 50% success in initiating luminal breast cancer organoids from tumor scrapes and maintaining them to the 14-day zero-passage endpoint. Success was mostly independent of clinical parameters, supporting general applicability of the approach. Abundance of ESR1 and PGR in zero-passage organoids consistently remained within the range of patient variability at the endpoint. However, responsiveness to hormone withdrawal and blockade was highly variable among luminal breast cancer cases tested. Combining sulforaphane with knockout of NQO1 (a phase II antioxidant response gene and downstream effector of sulforaphane) also yielded a breadth of organoid growth phenotypes, including growth inhibition with sulforaphane, growth promotion with NQO1 knockout, and growth antagonism when combined.</p><p><strong>Conclusions: </strong>Zero-passage organoids are a rapid and scalable way to interrogate properties of luminal breast cancer cells from patient-derived material. This includes testing drug mechanisms of action in different clinical cohorts. A future goal is to relate inter-patient variability of zero-passage organoids to long-term outcomes.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"192"},"PeriodicalIF":7.4,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911009","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":"GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis.","authors":"Wen-Ke Wang, Hui-Yu Lin, Che-Hsuan Lin, Hsun-Hua Lee, Yen-Lin Chen, Yu-Hsien Kent Lin, Hui-Wen Chiu, Shry-Ming Sheen-Chen, Yuan-Feng Lin","doi":"10.1186/s13058-024-01953-z","DOIUrl":"10.1186/s13058-024-01953-z","url":null,"abstract":"<p><strong>Background: </strong>Triple negative breast cancer (TNBC) belongs to the worst prognosis of breast cancer subtype probably because of distant metastasis to other organs, e.g. lungs. However, the mechanism underlying TNBC metastasis remains largely unknown.</p><p><strong>Methods: </strong>Bioinformatics analysis was conducted to evaluate the mRNA/protein expression and prognostic significance of G protein-coupled receptor kinase 6 (GRK6) in BC subtypes. RT-PCR assays were used to test the GRK6 expression in human BC tissues and cell lines. The in vitro cellular migration and in vivo lung colony-forming assays were established to estimate the metastatic potentials of TNBC cells. Western blotting was employed to examine protein phosphorylation, translocation and expression in the designed experiments.</p><p><strong>Results: </strong>Here we show that GRK6 upregulation is extensively detected in TNBC compared to normal mammary tissues and other BC subtypes and correlates with an increased risk for distant metastasis in TNBC patients. GRK6 knockdown suppressed but overexpression potentiated the cellular migration and lung colony-forming abilities of TNBC cells. Moreover, our data demonstrated that the posttranslational palmitoylation of GRK6 is extremely critical for activating β-Arrestin 2/mitogen-activated protein kinases (MAPKs)/NF-κB signaling axis and fostering the metastatic potentials of TNBC cells. Accordingly, the pharmaceutical inhibition of GRK6 kinase activity dramatically suppressed the activation of β-Arrestin 2, MAPKs and NF-κB and the cellular migration ability of highly metastatic MDA-MB231 cells. Sequentially blocking the β-Arrestin 2/MAPKs/NF-κB axis with their inhibitors predominantly mitigated the GRK6-promoted migration ability of poorly metastatic HCC1937 cells.</p><p><strong>Conclusion: </strong>Our results not only provide a novel mechanism for TNBC metastasis but also offer a new therapeutic strategy to combat metastatic TNBC via targeting GRK6 activity.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"193"},"PeriodicalIF":7.4,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11689595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911007","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":"G-cleave LC3B biosensor: monitoring autophagy and assessing resveratrol's synergistic impact on doxorubicin-induced apoptosis in breast cancer cells.","authors":"Chiao-Chun Liao, Yuqing Long, Ming-Lin Tsai, Chun-Yu Lin, Kai-Wen Hsu, Chia-Hwa Lee","doi":"10.1186/s13058-024-01951-1","DOIUrl":"10.1186/s13058-024-01951-1","url":null,"abstract":"<p><p>Autophagy, a crucial process in cancer, is closely intertwined with both tumor progression and drug resistance development. However, existing methods used to assess autophagy activity often pose invasiveness and time-related constraints, limiting their applicability in preclinical drug investigations. In this study, we developed a non-invasive autophagy detection system (NIADS-autophagy, also called G-cleave LC3B biosensor) by integrating a split-luciferase-based biosensor with an LC3B cleavage sequence, which swiftly identified classic autophagic triggers, such as Earle's Balanced Salt Solution and serum deprivation, through protease-mediated degradation pathways. The specificity of G-cleave LC3B biosensor was confirmed via CRISPR gene editing of pivotal autophagy regulator ATG4B, yielding diminished luciferase activity in MDA-MB-231 breast cancer cells. Notably, the G-cleave LC3B biosensor exhibited strong concordance with established autophagy metrics, encompassing LC3B lipidation, SQSTM1 degradation, and puncta accumulation analysis. To underscore the usage potential of the G-cleave LC3B biosensor, we discovered that resveratrol acts as a synergistic enhancer by significantly potentiating apoptosis in MDA-MB-231 cells when combined with doxorubicin treatment. Overall, the luminescence-based G-cleave LC3B biosensor presents a rapid and dependable avenue for determining autophagy activity, thereby facilitating high-throughput assessment of promising autophagy-associated anti-cancer therapies across diverse malignancies.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"190"},"PeriodicalIF":7.4,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907633","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":"Surgical delay-associated mortality risk varies by subtype in loco-regional breast cancer patients in SEER-Medicare.","authors":"Macall Leslie Salewon, Rashmi Pathak, William C Dooley, Ronald A Squires, Hallgeir Rui, Inna Chervoneva, Takemi Tanaka","doi":"10.1186/s13058-024-01949-9","DOIUrl":"10.1186/s13058-024-01949-9","url":null,"abstract":"<p><p>Substantial evidence supports that delay of surgery after breast cancer diagnosis is associated with increased mortality risk, leading to the introduction of a new Commission on Cancer quality measure for receipt of surgery within 60 days of diagnosis for non-neoadjuvant patients. Breast cancer subtype is a critical prognostic factor and determines treatment options; however, it remains unknown whether surgical delay-associated breast cancer-specific mortality (BCSM) risk differs by subtype. This retrospective cohort study aimed to assess whether the impact of delayed surgery on survival varies by subtype (hormone [HR] + /HER2 -, HR -/HER2 -, and HER2 +) in patients with loco-regional breast cancer who received surgery as their first treatment between 2010 and 2017 using the SEER-Medicare database. Exposure of this study was continuous time to surgery from diagnostic biopsy (TTS; days) in reference to TTS = 30 days. BCSM were evaluated as flexibly dependent on continuous time (days) to surgery from diagnosis (TTS) using Fine and Gray competing-risk regression models, respectively, by HR status. Inverse propensity score-weighting was adjusted for demographic, clinical, and treatment variables impacting TTS. Adjusted BCSM risk grew with increasing TTS across all subtypes; however, the pattern and extent of the association varied. HR + /HER2 - patients exhibited the most pronounced increase in BCSM risk associated with TTS, with approximately exponential growth after 42 days, with adjusted subdistribution hazard ratios (sHR) of 1.21 (95% CI: 1.06-1.37) at TTS = 60 days, 1.79 (95% CI: 1.40-2.29) at TTS = 90 days, and 2.83 (95% CI: 1.76-4.55) at TTS = 120 days. In contrast, both HER2 + and HR -/HER2 - patients showed slower, approximately linear growth in sHR, although non-significant in HR -HER2 -.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"191"},"PeriodicalIF":7.4,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907634","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":"Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction.","authors":"Kristia Yiangou, Nasim Mavaddat, Joe Dennis, Maria Zanti, Qin Wang, Manjeet K Bolla, Mustapha Abubakar, Thomas U Ahearn, Irene L Andrulis, Hoda Anton-Culver, Natalia N Antonenkova, Volker Arndt, Kristan J Aronson, Annelie Augustinsson, Adinda Baten, Sabine Behrens, Marina Bermisheva, Amy Berrington de Gonzalez, Katarzyna Białkowska, Nicholas Boddicker, Clara Bodelon, Natalia V Bogdanova, Stig E Bojesen, Kristen D Brantley, Hiltrud Brauch, Hermann Brenner, Nicola J Camp, Federico Canzian, Jose E Castelao, Melissa H Cessna, Jenny Chang-Claude, Georgia Chenevix-Trench, Wendy K Chung, Sarah V Colonna, Fergus J Couch, Angela Cox, Simon S Cross, Kamila Czene, Mary B Daly, Peter Devilee, Thilo Dörk, Alison M Dunning, Diana M Eccles, A Heather Eliassen, Christoph Engel, Mikael Eriksson, D Gareth Evans, Peter A Fasching, Olivia Fletcher, Henrik Flyger, Lin Fritschi, Manuela Gago-Dominguez, Aleksandra Gentry-Maharaj, Anna González-Neira, Pascal Guénel, Eric Hahnen, Christopher A Haiman, Ute Hamann, Jaana M Hartikainen, Vikki Ho, James Hodge, Antoinette Hollestelle, Ellen Honisch, Maartje J Hooning, Reiner Hoppe, John L Hopper, Sacha Howell, Anthony Howell, Simona Jakovchevska, Anna Jakubowska, Helena Jernström, Nichola Johnson, Rudolf Kaaks, Elza K Khusnutdinova, Cari M Kitahara, Stella Koutros, Vessela N Kristensen, James V Lacey, Diether Lambrechts, Flavio Lejbkowicz, Annika Lindblom, Michael Lush, Arto Mannermaa, Dimitrios Mavroudis, Usha Menon, Rachel A Murphy, Heli Nevanlinna, Nadia Obi, Kenneth Offit, Tjoung-Won Park-Simon, Alpa V Patel, Cheng Peng, Paolo Peterlongo, Guillermo Pita, Dijana Plaseska-Karanfilska, Katri Pylkäs, Paolo Radice, Muhammad U Rashid, Gad Rennert, Eleanor Roberts, Juan Rodriguez, Atocha Romero, Efraim H Rosenberg, Emmanouil Saloustros, Dale P Sandler, Elinor J Sawyer, Rita K Schmutzler, Christopher G Scott, Xiao-Ou Shu, Melissa C Southey, Jennifer Stone, Jack A Taylor, Lauren R Teras, Irma van de Beek, Walter Willett, Robert Winqvist, Wei Zheng, Celine M Vachon, Marjanka K Schmidt, Per Hall, Robert J MacInnis, Roger L Milne, Paul D P Pharoah, Jacques Simard, Antonis C Antoniou, Douglas F Easton, Kyriaki Michailidou","doi":"10.1186/s13058-024-01947-x","DOIUrl":"10.1186/s13058-024-01947-x","url":null,"abstract":"<p><strong>Background: </strong>The 313-variant polygenic risk score (PRS₃₁₃) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS₃₁₃ across different European populations which could influence risk estimation has not been performed.</p><p><strong>Methods: </strong>We explored the distribution of PRS₃₁₃ across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank. The mean PRS was calculated by country in the BCAC dataset and by country of birth in the UK Biobank. We explored different approaches to reduce the observed heterogeneity in the mean PRS across the countries, and investigated the implications of the distribution variability in risk prediction.</p><p><strong>Results: </strong>The mean PRS₃₁₃ differed markedly across European countries, being highest in individuals from Greece and Italy and lowest in individuals from Ireland. Using the overall European PRS₃₁₃ distribution to define risk categories, leads to overestimation and underestimation of risk in some individuals from these countries. Adjustment for principal components explained most of the observed heterogeneity in the mean PRS. The mean estimates derived when using an empirical Bayes approach were similar to the predicted means after principal component adjustment.</p><p><strong>Conclusions: </strong>Our results demonstrate that PRS distribution differs even within European ancestry populations leading to underestimation or overestimation of risk in specific European countries, which could potentially influence clinical management of some individuals if is not appropriately accounted for. Population-specific PRS distributions may be used in breast cancer risk estimation to ensure predicted risks are correctly calibrated across risk categories.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"189"},"PeriodicalIF":7.4,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11682615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903914","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":"Depression risk among breast cancer survivors: a nationwide cohort study in South Korea.","authors":"Hea Lim Choi, Su Min Jeong, Keun Hye Jeon, Bongseong Kim, Wonyoung Jung, Ansuk Jeong, Kyungdo Han, Dong Wook Shin","doi":"10.1186/s13058-024-01948-w","DOIUrl":"10.1186/s13058-024-01948-w","url":null,"abstract":"<p><strong>Background: </strong>Depression among breast cancer survivors is a significant concern affecting their long-term survivorship and quality of life. This study investigates the incidence of depression among breast cancer survivors and identifies associated risk factors.</p><p><strong>Methods: </strong>This retrospective cohort study used data from the Korean National Health Insurance Service database and included 59,340 breast cancer patients without a history of depression who underwent surgery between January 1, 2010, and December 31, 2016. They were individually matched 1:2 by age with a general population without cancer (n = 99,834). The mean follow-up period was 6.4 ± 2.6 years. Sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs) were calculated considering death as a competing risk and adjusting for sociodemographic factors and comorbidities.</p><p><strong>Results: </strong>Breast cancer survivors with a mean (standard deviation) age of 51.5 (9.2) years had a 39% increased risk of depression compared to non-cancer controls (sHR 1.39, 95% CI 1.36-1.42). During the first year post-diagnosis, breast cancer survivors across all ages exhibited a significantly elevated risk of depression, with a sHR of 3.23 (95% CI 3.08-3.37). Notably, younger survivors had a sHR of 4.51 (95% CI 4.19-4.85), and older survivors had a sHR of 2.56 (95% CI 2.42-2.71). One year post-surgery, younger survivors (age ≤ 50 years) showed a 1.16-fold increase in depression risk (sHR 1.16, 95% CI 1.11-1.20), while older survivors (age > 50 years) showed no significant change in risk, which decreased over time. Use of anthracycline, taxane, or endocrine therapy was associated with an increased depression risk (sHR 1.17, 95% CI 1.13-1.22; sHR 1.12, 95% CI 1.07-1.16; and sHR 1.27, 95% CI 1.14-1.41, respectively), with endocrine therapy showing a 41% increased depression risk in older survivors (sHR 1.41, 95% CI 1.23-1.61).</p><p><strong>Conclusion: </strong>This study demonstrates a significant association between breast cancer and depression, with a particularly heightened risk in younger survivors within the first year post-diagnosis. Special attention is needed to meticulously screen for depressive symptoms during the early follow-up years for breast cancer survivors who are premenopausal or have undergone chemotherapy and endocrine therapy.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"188"},"PeriodicalIF":7.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11674164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899744","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":"Cilengitide sensitivity is predicted by overall integrin expression in breast cancer.","authors":"Nomeda Girnius, Aylin Z Henstridge, Benjamin Marks, Jeffrey K Yu, G Kenneth Gray, Chris Sander, Ioannis K Zervantonakis, Augustin Luna","doi":"10.1186/s13058-024-01942-2","DOIUrl":"10.1186/s13058-024-01942-2","url":null,"abstract":"<p><strong>Background: </strong>Treatment options for triple-negative breast cancer (TNBC) are limited and patients face a poor prognosis. Here, we sought to identify drugs that target TNBC vulnerabilities and understand the biology underlying these responses. We analyzed the Broad Institute DepMap to identify recurrent TNBC vulnerabilities and performed a 45-compound screen on vulnerability-related pathways on a set of up to 8 TNBC cell lines. We identified a subset of cell lines with an ITGAV vulnerability and a differential sensitivity to cilengitide, an integrin inhibitor targeting ITGAV:ITGB3 and ITGAV:ITGB5. Next, we sought to understand cilengitide resistance and response biomarkers. Clinical trials targeting integrins continue enrolling patients, necessitating an understanding of how these drugs affect tumors.</p><p><strong>Methods: </strong>We combined in vitro assays with computational approaches to systematically explore the differential sensitivity to cilengitide and resistance mechanisms. We tested an additional pan-ITGAV inhibitor (GLPG0187) to determine how generalizable our findings on cilengitide sensitivity might be to integrin inhibition. ITGB4, ITGA3, and ITGA6 knockdown experiments assessed the importance of integrin monomers in cell attachment during cilengitide treatment. Additionally, we explored the role of extracellular matrix (ECM) proteins in cilengitide response by performing cell replating experiments and by culturing on collagen, fibronectin, or laminin coated plates.</p><p><strong>Results: </strong>We discovered that cell-derived ECM modulates cilengitide sensitivity and exogenous fibronectin addition conferred resistance to all sensitive TNBC cell lines, though fibronectin expression did not correlate with sensitivity. Instead, elevated overall integrin protein levels, not specific integrins, in TNBC cells positively correlated with resistance. This suggested that high pan-integrin expression promotes cilengitide resistance. Thus, we tested cilengitide in six luminal breast cancer cell lines (which have low integrin levels); all were sensitive. Also, pan-ITGAV inhibitor, GLPG0187, showed the same sensitivity profile across our TNBC cell lines, suggesting our findings apply to other integrin inhibitors.</p><p><strong>Conclusions: </strong>Integrin inhibitors are appealing candidates to pursue as anti-cancer drugs because they are generally well-tolerated, but their efficacy is mixed, possibly due to the absence of predictive markers. Cilengitide induces death in breast cancer cells with low integrin abundance, where complementary ECM promotes survival. Thus, integrin inhibition in breast cancer warrants further study.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"187"},"PeriodicalIF":7.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873092","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":"A hybrid epithelial-mesenchymal transition program enables basal epithelial cells to bypass stress-induced stasis and contributes to a metaplastic breast cancer progenitor state.","authors":"Joseph A Caruso, Chira Chen-Tanyolac, Thea D Tlsty","doi":"10.1186/s13058-024-01920-8","DOIUrl":"10.1186/s13058-024-01920-8","url":null,"abstract":"<p><strong>Background: </strong>Human mammary epithelial cell (HMEC) cultures encounter a stress-associated barrier termed stasis, during which most cells adopt a senescence-like phenotype. From these cultures, rare variants emerge from the basal epithelial population, re-initiating growth. Variants exhibit pre-malignant properties, including an aberrant epigenetic program that enables continued proliferation and acquisition of genetic changes. Following oncogenic transformation, variants produce tumors that recapitulate the histopathological characteristics of metaplastic breast cancer (MBC), a rare and aggressive subtype marked by the differentiation of neoplastic epithelium into squamous and mesenchymal elements.</p><p><strong>Methods: </strong>Using a serum-free HMEC culture system, we probed the capacity for phenotypic plasticity inherent to basal epithelial cell populations from human breast tissue as they navigated stasis and emerged as variant populations.</p><p><strong>Results: </strong>We observed robust activation of a TGF-β-dependent epithelial-mesenchymal transition (EMT) program in basal epithelial cells during stasis, followed by subsequent attenuation of this program in emerging variants. Inhibition of the TGF-β pathway or depleting the EMT regulators Snail or Slug allowed basal epithelial cells to collectively bypass stasis, demonstrating that cellular dysfunction and arrest resulting from TGF-β and EMT activation are central to this in vitro barrier. The spontaneous emergence of variants from stasis cultures was associated with a restricted EMT trajectory, characterized by the stabilization of hybrid EMT states associated with greater proliferative capacity, rather than progressing to a complete mesenchymal state characterized by irreversible growth arrest. Epigenetic mechanisms, which contributed to the dysregulated growth control characteristic of the variant phenotype, also contributed to the stability of the hybrid EMT program in variants. By overcoming the cellular dysfunction and growth arrest resulting from TGF-β and complete EMT, variants exhibited a higher oncogenic transformation efficiency compared to pre-stasis basal epithelial cells. Inhibiting the TGF-β pathway prior to stasis significantly reduced EMT in the basal epithelial population, alleviated selective pressure driving variant emergence, and also enhanced oncogenic transformation efficiency, resulting in tumors with markedly diminished metaplastic differentiation.</p><p><strong>Conclusions: </strong>This study reveals how an epigenetic program governs basal epithelial cell fate decisions and contributes to the development of MBC progenitors by restricting access to terminal mesenchymal states that induce growth arrest and, instead, favoring hybrid EMT states with enhanced tumorigenic potential.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"184"},"PeriodicalIF":7.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856234","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":"ERBB2/HOXB13 co-amplification with interstitial loss of BRCA1 defines a unique subset of breast cancers.","authors":"Irene Rin Mitsiades, Maristela Onozato, A John Iafrate, Daniel Hicks, Doğa C Gülhan, Dennis C Sgroi, Esther Rheinbay","doi":"10.1186/s13058-024-01943-1","DOIUrl":"10.1186/s13058-024-01943-1","url":null,"abstract":"<p><strong>Background: </strong>The HOXB13/IL17RB gene expression biomarker has been shown to predict response to adjuvant and extended endocrine therapy in patients with early-stage ER+ HER2- breast tumors. HOXB13 gene expression is the primary determinant driving the prognostic and endocrine treatment-predictive performance of the biomarker. Currently, there is limited data on HOXB13 expression in HER2+ and ER- breast cancers. Herein, we studied the expression of HOXB13 in large cohorts of HER2+ and ER- breast cancers.</p><p><strong>Methods: </strong>We investigated gene expression, genomic copy number, mutational signatures, and clinical outcome data in the TGGA and METABRIC breast cancer cohorts. Genomic-based gene amplification data was validated with tri-colored fluorescence in situ hybridization.</p><p><strong>Results: </strong>In the TCGA breast cancer cohort, HOXB13 gene expression was significantly higher in HER2+ versus HER2- breast cancers, and its expression was also significantly higher in the ER- versus ER+ breast cancers. HOXB13 is frequently co-gained or co-amplified with ERBB2. Joint copy gains of HOXB13 and ERBB2 occurred with low-level co-gains or high-level co-amplifications (co-amp), the latter of which is associated with an interstitial loss that includes the tumor suppressor BRCA1. ERBB2/HOXB13 co-amp tumors with interstitial BRCA1 loss exhibit a mutational signature associated with APOBEC deaminase activity and copy number signatures associated with chromothripsis and genomic instability. Among ERBB2-amplified tumors of different tissue origins, ERBB2/HOXB13 co-amp with a BRCA1 loss appeared to be enriched in breast cancer compared to other tumor types. Lastly, patients with ERBB2/HOXB13 co-amplified and BRCA1 lost tumors displayed a significantly shorter progression-free survival (PFS) than those with ERBB2-only amplifications. The difference in PFS was restricted to the ER- subset patients and this difference in PFS was not solely driven by HOXB13 gene expression.</p><p><strong>Conclusions: </strong>HOXB13 is frequently co-gained with ERBB2 at both low-copy number level or as complex high-level amplification with relative BRCA1 loss. ERBB2/HOXB13 amplified, BRCA1-lost tumors are strongly enriched in breast cancer, and patients with such breast tumors experience a shortened PFS.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"185"},"PeriodicalIF":7.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856237","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}