Breast Cancer Research最新文献

{"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}

{"title":"Intraoperative radiotherapy versus whole breast radiotherapy in early-stage breast cancer: a retrospective outcome analysis based on ASTRO guidelines on PBI.","authors":"Shi-Yu Gao, Ting-Chun Lin, Liang-Chih Liu, Wen-Ling Chen, Ji-An Liang","doi":"10.1186/s13058-024-01936-0","DOIUrl":"10.1186/s13058-024-01936-0","url":null,"abstract":"<p><strong>Background: </strong>Intraoperative radiotherapy (IORT) is a convenient treatment techniques for patients with early-stage breast cancer. We aimed to compare the outcome of IORT to that of whole-breast external beam radiotherapy (EBRT) in highly selected breast cancer patients based on the 2023 American Society for Radiation Oncology (ASTRO) Clinical Practice Guideline for Partial Breast Irradiation (PBI).</p><p><strong>Patients and methods: </strong>We reviewed patients who underwent breast-conserving surgery (BCS) and received either IORT or EBRT for early-stage breast cancer between 2014 and 2019. The outcomes of these patients were analyzed and compared across different risk stratifications according to the 2023 ASTRO Clinical Practice Guideline for PBI, which categorized the patients into \"recommended\", \"conditionally recommended\", or \"conditionally not recommended\" groups.</p><p><strong>Results: </strong>A total of 732 patients were enrolled with a mean follow-up time of 5.1 years. Among patients in the recommended group, the locoregional recurrence rates were 2.0% for IORT and 2.3% for EBRT (p = 0.978). Conversely, in the conditionally recommended or conditionally not recommended groups, IORT exhibited significantly higher locoregional recurrence rates compared to EBRT: in the conditionally recommended group, IORT had a recurrence rate of 11.1% versus 3.0% for EBRT (p = 0.044), and in the conditionally not recommended group, IORT had a rate of 13.8% versus 2.5% for EBRT (p = 0.010).</p><p><strong>Conclusions: </strong>The locoregional recurrence rate in the IORT group was comparable to that of the EBRT group for patients recommended for PBI. However, for patients categorized as conditionally recommended or conditionally not recommended for PBI, the IORT group showed a higher locoregional recurrence rate, highlighting the need for careful patient selection.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"181"},"PeriodicalIF":7.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856242","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":"Protective effects of miR-24-2-5p in early stages of breast cancer bone metastasis.","authors":"Margherita Puppo, Martine Croset, Davide Ceresa, Manoj Kumar Valluru, Victor Gabriel Canuas Landero, Monserrat Hernandez Guadarrama, Michele Iuliani, Francesco Pantano, Penelope Dawn Ottewell, Philippe Clézardin","doi":"10.1186/s13058-024-01934-2","DOIUrl":"10.1186/s13058-024-01934-2","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Bone is the most frequent site of metastasis for breast cancer (BC). Metastatic BC cells interact with bone cells, including osteoclasts and osteoblasts, creating a cancer niche where they seed and proliferate. MicroRNAs (miRNAs) are regulators of breast-to-bone metastasis progression. MiR-24-2-5p has previously been shown to have roles in both breast cancer progression and inhibition of osteogenic differentiation. However, a direct link between miR-24-2-5p activity and the onset of bone metastasis remains ill-defined.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Analysis of the expression of miR-24 forms (miR-24-2-5p, miR-24-3p, miR-24-1-5p) in the serum from early-stage BC patients at baseline (time of surgery) was conducted. MiR-24-2-5p overexpression in BC cells (NW1, a luc2-positive subpopulation of MDA-MB-231, and MCF7) was obtained by miRNA mimic transfection or lentivirus transduction. MiR-24-2-5p downregulation in BC cells (ZR-75-1, T-47D, SK-BR-3) was obtained by miRNA inhibitor transfection. Cell proliferation, migration and/or invasion assays were performed to assess BC cell functions after modulation of miR-24-2-5p expression. An animal model was used to assess the effect of miR-24-2-5p overexpression on early BC metastasis formation, as judged by bioluminescence imaging, and on bone remodelling, following measurement of circulating bone resorption (CTX-I) and bone formation (P1NP) markers. The effect of conditioned medium from miR-24-2-5p-overexpressing BC cells on human and murine osteoclast differentiation was investigated. Endogenous miR-24-2-5p expression levels were also quantified during murine osteoclast differentiation. RNA-sequencing (RNA-seq) analysis of BC cells was performed to evaluate transcriptomic changes associated with miR-24-2-5p overexpression. Selected modulated transcripts upon miR-24-2-5p overexpression were further validated by real-time qPCR.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Low expression levels of miR-24-2-5p, but not other miR-24 forms (miR-24-3p, miR-24-1-5p), in the serum from early-stage BC patients were associated with a high risk to develop future (bone) metastases. MiR-24-2-5p was also present in small extracellular vesicles secreted from BC cells. Forced expression of miR-24-2-5p in BC cells (NW1, MCF7) reduced their malignant traits (migration, invasion, and proliferation) in vitro. Furthermore, miR-24-2-5p overexpression in NW1 cells reduced metastasis, particularly in bone, and decreased bone turnover in vivo. RNA-seq and real-time qPCR analyses of NW1 and MCF7 cells overexpressing miR-24-2-5p showed the downregulation of common transcripts (CNNM4, DCTD, FMR1, PIGS, HLA-A, ICK, SH3BGRL2, WDFY, TRAF9B, IL6ST, PEX10, TRIM59). The conditioned medium from BC cells overexpressing miR-24-2-5p decreased human and murine osteoclast differentiation in vitro. Additionally, endogenous miR-24-2-5p expression levels in murine bone marrow-derived monocytes decreased during their differentiat","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"186"},"PeriodicalIF":7.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11656574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856279","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":"Oncogene activated human breast luminal progenitors contribute basally located myoepithelial cells.","authors":"Katharina Theresa Kohler, Jiyoung Kim, René Villadsen, Lone Rønnov-Jessen, Ole William Petersen","doi":"10.1186/s13058-024-01939-x","DOIUrl":"10.1186/s13058-024-01939-x","url":null,"abstract":"<p><strong>Background: </strong>Basal-like breast cancer originates in luminal progenitors, frequently with an altered PI3K pathway, and focally in close association with genetically altered myoepithelial cells at the site of tumor initiation. The exact trajectory behind this bi-lineage phenomenon remains poorly understood.</p><p><strong>Methods and results: </strong>Here we used a breast cancer relevant transduction protocol including hTERT, shp16, shp53, and PIK3CA^H1047R to immortalize FACS isolated luminal cells, and we identified a candidate multipotent progenitor. Specifically, we identified a keratin 23 (K23)⁺/ALDH1A3⁺/CALML5^- ductal-like progenitor with the potential to differentiate into CALML5⁺ lobular-like cells. We found that the apparent luminal phenotype of these oncogene transduced progenitors was metastable giving rise to basal-like cells dependent on culture conditions. In 3D organoid culture and upon transplantation to mice the bipotent progenitor cell line organized into a bi-layered acinus-like structure reminiscent of that of the normal breast gland.</p><p><strong>Conclusions: </strong>These findings provide proof of principle that progenitors within the human breast luminal epithelial compartment may serve as a source of correctly positioned myoepithelial cells. This may prove useful in assessing the role of myoepithelial cells in breast tumor progression.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"183"},"PeriodicalIF":7.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11656586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856244","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":"Stromal tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: a single-center real-world study.","authors":"Soong June Bae, Jee Hung Kim, Min Ji Kim, Yoonwon Kook, Seung Ho Baek, Jung Hyun Kim, Sohyun Moon, Seung Eun Lee, Joon Jeong, Yoon Jin Cha, Sung Gwe Ahn","doi":"10.1186/s13058-024-01944-0","DOIUrl":"10.1186/s13058-024-01944-0","url":null,"abstract":"<p><strong>Background: </strong>Immunochemotherapy with pembrolizumab has been integrated into clinical practice as part of the standard-of-care for non-metastatic triple-negative breast cancer (TNBC) with high risk. We conducted a real-world study in TNBC patients treated with neoadjuvant chemotherapy to compare pathologic complete response (pCR) rates relative to stromal tumor-infiltrating lymphocytes (sTIL) across different regimens: non-carboplatin, carboplatin-, and pembrolizumab-chemotherapy.</p><p><strong>Patients and methods: </strong>We analyzed a cohort of 450 patients with TNBC who underwent surgery following neoadjuvant chemotherapy between March 2007 and February 2024. Treatment groups included 247 non-carboplatin, 120 carboplatin, and 83 pembrolizumab-chemotherapy recipients. sTIL was evaluated in biopsied samples. Lymphocyte-predominant breast cancer (LPBC) was defined as tumors with high sTIL (≥ 50%).</p><p><strong>Results: </strong>The pCR rates were 32% in the non-carboplatin-, 57% in the carboplatin-, and 64% in the pembrolizumab-chemotherapy group. Ninety-two patients (20.4%) had LPBC. In LPBC, the pCR rates did not increase with the addition of carboplatin (50.0% in the non-carboplatin and 41.7% in carboplatin) but reached 83.3% with the addition of pembrolizumab and carboplatin. Among the non-LPBC, the pCR rate increased from 26.7 to 61.1% with the addition of carboplatin, but there was no difference in the pCR rate between the carboplatin and pembrolizumab groups (61.1% and 61.2%, respectively).</p><p><strong>Conclusions: </strong>In LPBC patients, the addition of carboplatin did not result in an elevated pCR rate; however, the addition of pembrolizumab tended to raise the pCR rate. In non-LPBC, the addition of carboplatin significantly increased the pCR rate, while the addition of pembrolizumab did not have the same effect.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"182"},"PeriodicalIF":7.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856283","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":"Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancer.","authors":"Eunkyung Han, Hye Yeon Choi, Hyun Jung Kwon, Yul Ri Chung, Hee-Chul Shin, Eun-Kyu Kim, Koung Jin Suh, Se Hyun Kim, Jee Hyun Kim, So Yeon Park","doi":"10.1186/s13058-024-01932-4","DOIUrl":"10.1186/s13058-024-01932-4","url":null,"abstract":"<p><strong>Background: </strong>The tumor immune microenvironment, particularly tumor-infiltrating lymphocytes (TILs), plays a critical role in disease progression and treatment response in triple-negative breast cancers (TNBCs). This study was aimed to characterize the composition of TILs and investigate their clinicopathological and prognostic significance with a special focus on the spatial distribution of TILs in TNBCs.</p><p><strong>Methods: </strong>We analyzed TNBC samples through PanCancer Immune Profiling using NanoString nCounter assays to identify immune-related genes that are expressed differentially in relation to TIL levels and evaluated protein expression of selected markers through immunohistochemical staining on tissue microarrays. For a comprehensive assessment of the expression of cytotoxic T lymphocyte (CTL) and natural killer (NK) cell markers, a CTL-NK score was devised based on CD8⁺, CD56⁺, CD57⁺, GNLY⁺, and GZMB⁺ TIL levels.</p><p><strong>Results: </strong>Gene expression analysis revealed significant upregulation of CTL and NK cell-associated genes including GNLY, KLRC2, and GZMB in TIL-high TNBCs. Immunohistochemical validation confirmed that TNBCs with higher TILs had a greater amount of CD56⁺, CD57⁺, GNLY⁺, and GZMB⁺ TILs not only in absolute number but also in proportion relative to CD4⁺ or CD8⁺ TILs. High TIL and its subset (CD4⁺, CD8⁺, CD56⁺, CD57⁺, GNLY⁺, and GZMB⁺ TIL) infiltration correlated with favorable clinicopathological features of tumor. In survival analysis, high CTL-NK score was found to be an independent prognostic factor for better disease-free survival (DFS) of the patients. Furthermore, uniformly high TIL infiltration was linked to better DFS, whereas cases with heterogeneous TIL infiltration showed no difference in survival compared to those with uniformly low TIL infiltration.</p><p><strong>Conclusion: </strong>Our study showed that CTL and NK cell-associated gene expression and protein levels differ significantly according to TIL levels and that CTL-NK score and distribution of TILs within tumors have a prognostic value. These findings emphasize the importance of CTLs and NK cells as well as the spatial uniformity of TIL infiltration in clinical outcome of TNBC patients, providing valuable insights for refining prognostic assessments and guiding immunotherapeutic strategies.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"180"},"PeriodicalIF":7.4,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792600","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":"Alcohol cessation and breast cancer risk stratified by hormone receptor status.","authors":"Mary Beth Terry, Dallas R English, Jo L Freudenheim, Béatrice Lauby-Secretan, Susan M Gapstur","doi":"10.1186/s13058-024-01937-z","DOIUrl":"10.1186/s13058-024-01937-z","url":null,"abstract":"<p><p>Because alcohol consumption is an established cause of female breast cancer, understanding whether cessation affects risk is of public health importance. In a recent meta-analysis, compared with continuing consumption, the relative risk (RR) for cessation was 0.95 (95% confidence interval [CI] 0.88-1.01). Because intake of alcohol is more consistently associated with estrogen receptor positive (ER+) than negative (ER-) subtypes, we conducted a meta-analysis of alcohol cessation for ER-specific breast cancer risk using data from three cohort studies and one population-based case-control study (ER + n = 3,793; ER- n = 627) with information reported on cessation and ER status. Compared with continuing consumption, cessation was associated with lower risk of ER+ (RR = 0.88, 95%CI, 0.79-0.98) but not ER- (RR = 1.23, 95%CI, 0.98-1.55) breast cancer. These results suggest that, compared with continuing consumption, alcohol cessation may reduce ER + but not ER- breast cancer risk. However, research that considers duration of cessation is warranted.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"179"},"PeriodicalIF":7.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787422","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":"Multimodal genome-wide survey of progressing and non-progressing breast ductal carcinoma in-situ.","authors":"Marija Debeljak, Soonweng Cho, Bradley M Downs, Michael Considine, Brittany Avin-McKelvey, Yongchun Wang, Phillip N Perez, William E Grizzle, Katherine A Hoadley, Charles F Lynch, Brenda Y Hernandez, Paul J van Diest, Wendy Cozen, Ann S Hamilton, Debra Hawes, Edward Gabrielson, Ashley Cimino-Mathews, Liliana D Florea, Leslie Cope, Christopher B Umbricht","doi":"10.1186/s13058-024-01927-1","DOIUrl":"10.1186/s13058-024-01927-1","url":null,"abstract":"<p><strong>Background: </strong>Ductal carcinoma in-situ (DCIS) is a pre-invasive form of invasive breast cancer (IBC). Due to improved breast cancer screening, it now accounts for ~ 25% of all breast cancers. While the treatment success rates are over 90%, this comes at the cost of considerable morbidity, considering that the majority of DCIS never become invasive and our understanding of the molecular changes occurring in DCIS that predispose to invasive disease is limited. The aim of this study is to characterize molecular changes that occur in DCIS, with the goal of improving DCIS risk stratification.</p><p><strong>Methods: </strong>We identified and obtained a total of 197 breast tissue samples from 5 institutions (93 DCIS progressors, 93 DCIS non-progressors, and 11 adjacent normal breast tissues) that had at least 10-year follow-up. We isolated DNA and RNA from archival tissue blocks and characterized genome-wide mRNA expression, DNA methylation, DNA copy number variation, and RNA splicing variation.</p><p><strong>Results: </strong>We obtained all four genomic data sets in 122 of the 197 samples. Our intrinsic expression subtype-stratified analyses identified multiple molecular differences both between DCIS subtypes and between DCIS and IBC. While there was heterogeneity in molecular signatures and outcomes within intrinsic subtypes, several gene sets that differed significantly between progressing and non-progressing DCIS were identified by Gene Set Enrichment Analysis.</p><p><strong>Conclusion: </strong>DCIS is a molecularly highly heterogenous disease with variable outcomes, and the molecular events determining DCIS disease progression remain poorly defined. Our genome-wide multi-omic survey documents DCIS-associated alterations and reveals molecular heterogeneity within the intrinsic DCIS subtypes. Further studies investigating intrinsic subtype-stratified characteristics and molecular signatures are needed to determine if these may be exploitable for risk assessment and mitigation of DCIS progression. The highly significant associations of specific gene sets with IBC progression revealed by our Gene Set Enrichment Analysis may lend themselves to the development of a prognostic molecular score, to be validated on independent DCIS cohorts.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"178"},"PeriodicalIF":7.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11616160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780972","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}