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Breast cancer in women with previous gestational diabetes: a nationwide register-based cohort study. 曾患妊娠糖尿病妇女的乳腺癌:一项基于全国登记的队列研究。
IF 7.4 1区 医学
Breast Cancer Research Pub Date : 2024-11-04 DOI: 10.1186/s13058-024-01908-4
Maria Hornstrup Christensen, Christina Anne Vinter, Thomas Bastholm Olesen, Maria Houborg Petersen, Ellen Aagaard Nohr, Katrine Hass Rubin, Marianne Skovsager Andersen, Dorte Moeller Jensen
{"title":"Breast cancer in women with previous gestational diabetes: a nationwide register-based cohort study.","authors":"Maria Hornstrup Christensen, Christina Anne Vinter, Thomas Bastholm Olesen, Maria Houborg Petersen, Ellen Aagaard Nohr, Katrine Hass Rubin, Marianne Skovsager Andersen, Dorte Moeller Jensen","doi":"10.1186/s13058-024-01908-4","DOIUrl":"10.1186/s13058-024-01908-4","url":null,"abstract":"<p><strong>Background: </strong>Gestational diabetes mellitus (GDM) is a common pregnancy complication characterized by insulin resistance. A link has been suggested between insulin resistance and breast cancer, which is the most common cancer in women. Hence, women with previous GDM may be at increased risk of developing breast cancer, yet, the existing evidence is conflicting. This study explored the association between GDM and incident breast cancer, including age at cancer diagnosis. Additionally, we investigated the potential impact of severity of insulin resistance during pregnancy and of subsequent diabetes development on the breast cancer risk.</p><p><strong>Methods: </strong>We conducted a nationwide, register-based cohort study including all women giving birth in Denmark from 1997 to 2018. We defined GDM and breast cancer based on ICD-10 codes. Premenopausal and postmenopausal breast cancer was pragmatically defined as age at outcome < 50 years and ≥ 50 years, respectively. A proxy for severity of insulin resistance during pregnancy was based on insulin treatment; subsequent diabetes was defined as presence of ICD-10 codes and/or antidiabetic medication after pregnancy. The statistical analyses included Cox regression, logistic regression and t-test.</p><p><strong>Results: </strong>Of 708,121 women, 3.4% had GDM. The median follow-up period was 11.9 years (range 0-21.9). The overall breast cancer risk was comparable in women with and without previous GDM (adjusted hazard ratio 0.96 [95% CI 0.83-1.12]). Premenopausal and postmenopausal breast cancer risk also did not differ; however, women with previous GDM had a breast cancer diagnosis at younger age (42.6 vs. 43.5 years, p-value 0.01). All-cause mortality was similar regardless of GDM history. Severity of insulin resistance during pregnancy and subsequent diabetes did not affect breast cancer risk.</p><p><strong>Conclusions: </strong>This large, population-based cohort study showed no higher risk of incident breast cancer in women with previous GDM compared to women without previous GDM after a median of almost 12 years of follow-up. This was evident irrespective of menopausal state. The breast cancer risk was not influenced by the severity of insulin resistance during pregnancy and by subsequent diabetes development. Regardless of GDM history, attention towards prevention, early detection and treatment of breast cancer should be prioritized.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"150"},"PeriodicalIF":7.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142577077","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}
引用次数: 0
Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancer. 转录组分析发现浸润性小叶乳腺癌中富含 cAMP/PKA/CREB 信号。
IF 7.4 1区 医学
Breast Cancer Research Pub Date : 2024-10-30 DOI: 10.1186/s13058-024-01900-y
Susrutha Puthanmadhom Narayanan, Abdalla M Wedn, Osama Shiraz Shah, Jian Chen, Daniel D Brown, Priscilla F McAuliffe, Steffi Oesterreich, Adrian V Lee
{"title":"Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancer.","authors":"Susrutha Puthanmadhom Narayanan, Abdalla M Wedn, Osama Shiraz Shah, Jian Chen, Daniel D Brown, Priscilla F McAuliffe, Steffi Oesterreich, Adrian V Lee","doi":"10.1186/s13058-024-01900-y","DOIUrl":"10.1186/s13058-024-01900-y","url":null,"abstract":"<p><strong>Objective: </strong>Invasive lobular breast cancer (ILC) is the most common special type of breast cancer and has unique clinicopathological and molecular hallmarks that differentiate it from the more common invasive carcinoma-no special type (NST). Despite these differences, ILC and NST are treated as a single entity and there is a lack of ILC-targeted therapies. To fill this gap, we sought to identify novel molecular alterations in ILC that could be exploited for targeted therapies.</p><p><strong>Methods: </strong>Differential gene expression and Geneset Enrichment and Variation analyses were performed on RNA-seq data from three large public breast cancer databases-the Sweden Cancerome Analysis Network-Breast (SCAN-B; luminal A ILC N = 263, luminal A NST N = 1162), The Cancer Genome Atlas (TCGA; luminal A ILC N = 157, luminal A NST N = 307) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; luminal A ILC N = 65, luminal A NST N = 533). Pathways enriched in overlapping differentially expressed genes from these datasets were clustered using Jaccard similarity to identify pathways enriched in ILC. The cAMP/PKA/CREB signaling was studied in ILC, ILC-like and NST cell lines and patient-derived organoids (PDOs) using forskolin, an activator of the pathway.</p><p><strong>Results: </strong>Clinicopathological features of patients with ILC and NST in SCAN-B were similar to prior population-based studies. There was a consistent pattern of up-regulation of cAMP/PKA/CREB related signaling in ILC compared to NST in SCAN-B, TCGA and METABRIC. Treatment with forskolin resulted in a greater increase in phospho-CREB in ILC cell lines and organoids than NST. CRISPR deletion of CDH1 in NST cell lines did not alter response of cells to forskolin as measured by phospho-CREB. Forskolin treatment caused growth inhibition in ILC and NST, with ILC cell lines being more sensitive to forskolin-mediated growth inhibition.</p><p><strong>Conclusion: </strong>In three separate datasets, cAMP/PKA/CREB signaling was identified to be higher in ILC than NST. This in silico finding was validated in cell line and organoid models. Loss of CDH1 was not sufficient to mediate this phenotype. Future studies should investigate the mechanisms for differential cAMP/PKA/CREB signaling and the potential for therapeutic targeting in patients with ILC.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"149"},"PeriodicalIF":7.4,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548536","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}
引用次数: 0
Predicting pathologic complete response to neoadjuvant chemotherapy in breast cancer using a machine learning approach. 利用机器学习方法预测乳腺癌新辅助化疗的病理完全反应
IF 7.4 1区 医学
Breast Cancer Research Pub Date : 2024-10-29 DOI: 10.1186/s13058-024-01905-7
Fangyuan Zhao, Eric Polley, Julian McClellan, Frederick Howard, Olufunmilayo I Olopade, Dezheng Huo
{"title":"Predicting pathologic complete response to neoadjuvant chemotherapy in breast cancer using a machine learning approach.","authors":"Fangyuan Zhao, Eric Polley, Julian McClellan, Frederick Howard, Olufunmilayo I Olopade, Dezheng Huo","doi":"10.1186/s13058-024-01905-7","DOIUrl":"10.1186/s13058-024-01905-7","url":null,"abstract":"<p><strong>Background: </strong>For patients with breast cancer undergoing neoadjuvant chemotherapy (NACT), most of the existing prediction models of pathologic complete response (pCR) using clinicopathological features were based on standard statistical models like logistic regression, while models based on machine learning mostly utilized imaging data and/or gene expression data. This study aims to develop a robust and accessible machine learning model to predict pCR using clinicopathological features alone, which can be used to facilitate clinical decision-making in diverse settings.</p><p><strong>Methods: </strong>The model was developed and validated within the National Cancer Data Base (NCDB, 2018-2020) and an external cohort at the University of Chicago (2010-2020). We compared logistic regression and machine learning models, and examined whether incorporating quantitative clinicopathological features improved model performance. Decision curve analysis was conducted to assess the model's clinical utility.</p><p><strong>Results: </strong>We identified 56,209 NCDB patients receiving NACT (pCR rate: 34.0%). The machine learning model incorporating quantitative clinicopathological features showed the best discrimination performance among all the fitted models [area under the receiver operating characteristic curve (AUC): 0.785, 95% confidence interval (CI): 0.778-0.792], along with outstanding calibration performance. The model performed best among patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer (AUC: 0.817, 95% CI: 0.802-0.832); and by adopting a 7% prediction threshold, the model achieved 90.5% sensitivity and 48.8% specificity, with decision curve analysis finding a 23.1% net reduction in chemotherapy use. In the external testing set of 584 patients (pCR rate: 33.4%), the model maintained robust performance both overall (AUC: 0.711, 95% CI: 0.668-0.753) and in the HR+/HER2- subgroup (AUC: 0.810, 95% CI: 0.742-0.878).</p><p><strong>Conclusions: </strong>The study developed a machine learning model ( https://huolab.cri.uchicago.edu/sample-apps/pcrmodel ) to predict pCR in breast cancer patients undergoing NACT that demonstrated robust discrimination and calibration performance. The model performed particularly well among patients with HR+/HER2- breast cancer, having the potential to identify patients who are less likely to achieve pCR and can consider alternative treatment strategies over chemotherapy. The model can also serve as a robust baseline model that can be integrated with smaller datasets containing additional granular features in future research.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"148"},"PeriodicalIF":7.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548535","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}
引用次数: 0
Effect of genistein supplementation on microenvironment regulation of breast tumors in obese mice. 补充染料木素对肥胖小鼠乳腺肿瘤微环境调控的影响
IF 7.4 1区 医学
Breast Cancer Research Pub Date : 2024-10-25 DOI: 10.1186/s13058-024-01904-8
Shengzi Jin, Yingce Zheng, Ding Li, Xingyao Liu, Tingting Zhu, Shuang Wang, Zhonghua Liu, Yun Liu
{"title":"Effect of genistein supplementation on microenvironment regulation of breast tumors in obese mice.","authors":"Shengzi Jin, Yingce Zheng, Ding Li, Xingyao Liu, Tingting Zhu, Shuang Wang, Zhonghua Liu, Yun Liu","doi":"10.1186/s13058-024-01904-8","DOIUrl":"10.1186/s13058-024-01904-8","url":null,"abstract":"<p><p>Obesity is an important risk factor for breast cancer in women before and after menopause. Adipocytes, key mediators in the tumor microenvironment, play a pivotal role in the relationship between obesity with cancer. However, the potential of dietary components in modulating this relationship remains underexplored. Genistein, a soy-derived isoflavone, has shown promise in reducing breast cancer risk, attenuating obesity-associated inflammation, and improving insulin resistance. However, there are no reports examining whether genistein has the ability to reduce the effects of obesity on breast tumor development. In this study, we constructed a mammary tumor model in ovariectomized obese mice and examined the effects of genistein on body condition and tumor growth. Moreover, the effects of genistein on the tumor microenvironment were examined via experimental observation of peritumoral adipocytes and macrophages. In addition, we further investigated the effect of genistein on adipocyte and breast cancer cell crosstalk via coculture experiments. Our findings indicate that dietary genistein significantly alleviates obesity, systemic inflammation, and metabolic disorders induced by a high-fat diet in ovariectomized mice. Notably, it also inhibits tumor growth in vivo. The impact of genistein extends to the tumor microenvironment, where it reduces the production of cancer-associated adipocytes (CAAs) and the recruitment of M2d-subtype macrophages. In vitro, genistein mitigates the transition of adipocytes into CAAs and inhibits the expression of inflammatory factors by activating PPAR-γ pathway and degrading nuclear NF-κB. Furthermore, it impedes the acquisition of invasive properties and epithelial‒mesenchymal transition in breast cancer cells under CAA-induced inflammation, disrupting the Wnt3a/β-catenin pathway. Intriguingly, the PPAR-γ inhibitor T0070907 counteracted the effects of genistein in the coculture system, underscoring the specificity of its action. Our study revealed that genistein can mitigate the adverse effects of obesity on breast cancer by modulating the tumor microenvironment. These findings provide new insights into how genistein intake and a soy-based diet can reduce breast cancer risk.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"147"},"PeriodicalIF":7.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511444","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}
引用次数: 0
Ribosomal S6 kinase (RSK) plays a critical role in DNA damage response via the phosphorylation of histone lysine demethylase KDM4B. 核糖体 S6 激酶(RSK)通过磷酸化组蛋白赖氨酸去甲基化酶 KDM4B,在 DNA 损伤反应中发挥着关键作用。
IF 7.4 1区 医学
Breast Cancer Research Pub Date : 2024-10-21 DOI: 10.1186/s13058-024-01901-x
Wenwen Wu, Jing Zhu, Naoe Taira Nihira, Yukiko Togashi, Atsushi Goda, Junki Koike, Kiyoshi Yamaguchi, Yoichi Furukawa, Takuya Tomita, Yasushi Saeki, Yoshikazu Johmura, Makoto Nakanishi, Yasuo Miyoshi, Tomohiko Ohta
{"title":"Ribosomal S6 kinase (RSK) plays a critical role in DNA damage response via the phosphorylation of histone lysine demethylase KDM4B.","authors":"Wenwen Wu, Jing Zhu, Naoe Taira Nihira, Yukiko Togashi, Atsushi Goda, Junki Koike, Kiyoshi Yamaguchi, Yoichi Furukawa, Takuya Tomita, Yasushi Saeki, Yoshikazu Johmura, Makoto Nakanishi, Yasuo Miyoshi, Tomohiko Ohta","doi":"10.1186/s13058-024-01901-x","DOIUrl":"10.1186/s13058-024-01901-x","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic dysregulation affecting oncogenic transcription and DNA damage response is a hallmark of cancer. The histone demethylase KDM4B, a factor regulating these processes, plays important roles in estrogen receptor-mediated transcription and DNA repair in breast cancer. However, how oncogenic phospho-signal transduction affects epigenetic regulation is not fully understood. Here we found that KDM4B phosphorylation by ribosomal S6 kinase (RSK), a downstream effector of the Ras/MAPK pathway, is critical for the function of KDM4B in response to DNA damage.</p><p><strong>Methods: </strong>KDM4B-knockout breast cancer cell lines were generated via CRISPR/Cas9-mediated gene editing. Re-expression of wild-type or phospho-site mutated KDM4B in knockout cells was performed by lentivirus-mediated gene transfer. Gene knockdown was achieved by RNA interference. DNA double-strand breaks (DSBs) were induced by ionizing radiation or laser-microirradiation. Protein accumulation at DSB sites was analyzed by immunofluorescence. KDM4B phosphorylation by RSK was assessed by in vitro and in vivo kinase assays. Gene and protein expression levels were analyzed by RT‒PCR and western blotting. The sensitivity of cells to ionizing radiation was examined by a clonogenic survival assay.</p><p><strong>Results: </strong>RSK phosphorylated KDM4B at Ser666, and inhibition of the phosphorylation by RSK depletion or RSK inhibitors abrogated KDM4B accumulation at the sites of DNA double-strand breaks (DSBs). DSB repair was significantly delayed in KDM4B-knockout cells or cells treated with RSK inhibitors. The replacement of endogenous KDM4B with the phosphomimetic mutant S666D restored KDM4B accumulation and DSB repair that had been inhibited by RSK inhibitors, suggesting a critical role for RSK at the specific serine residue of KDM4B in the effect of RSK inhibitors on DSB repair. As a consequence of these aberrant responses, inhibition of KDM4B phosphorylation increased the sensitivity of the cells to ionizing radiation.</p><p><strong>Conclusions: </strong>Overall, the present study uncovered a novel function of RSK on the DNA damage response, which provides an additional role of its inhibitor in cancer therapy.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"146"},"PeriodicalIF":7.4,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478899","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}
引用次数: 0
Disparities in receipt of 1-st line CDK4/6 inhibitors with endocrine therapy for treatment of hormone receptor positive, HER2 negative metastatic breast cancer in the real-world setting. 在现实世界中,激素受体阳性、HER2 阴性转移性乳腺癌患者接受 1 线 CDK4/6 抑制剂和内分泌疗法治疗的差异。
IF 7.4 1区 医学
Breast Cancer Research Pub Date : 2024-10-18 DOI: 10.1186/s13058-024-01902-w
Asal Pilehvari, Gretchen Kimmick, Wen You, Gloribel Bonilla, Roger Anderson
{"title":"Disparities in receipt of 1-<sup>st</sup> line CDK4/6 inhibitors with endocrine therapy for treatment of hormone receptor positive, HER2 negative metastatic breast cancer in the real-world setting.","authors":"Asal Pilehvari, Gretchen Kimmick, Wen You, Gloribel Bonilla, Roger Anderson","doi":"10.1186/s13058-024-01902-w","DOIUrl":"10.1186/s13058-024-01902-w","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;This study used real-world observational data to compare profiles of patients receiving different first-line treatment for hormone receptor positive (ER+), HER2 negative, metastatic breast cancer (MBC): CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) versus ET alone.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Method: &lt;/strong&gt;From a nationwide electronic health record-derived Flatiron Health de-identified database including 280 US cancer clinics, we identified patients with hormone receptor positive, HER2 negative, metastatic breast cancer receiving 1st -line therapy with ET alone or CDK4/6i plus ET between February 2015 and November 2021. Patient sociodemographic status, MBC treatment regimen and outcomes were the focus of this analysis. Patient characteristics were compared using t-tests and chi-square tests. Logistic regression analysis was performed to examine the association of patient characteristics with the likelihood of receiving 1st -line CDK4/6i plus ET vs. ET alone. Kaplan-Meier method and Cox proportional hazards were used to test the impact of 1st -line treatment regimen on real-world progression-free survival (PFS) and overall survival (OS). Baseline characteristics were balanced using inverse probability weighting (IPW).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The study population included 3,917 patients receiving CDK4/6i plus ET (n = 2170) and ET alone (n = 1747) for their MBC. Compared to patients receiving ET alone, those receiving CDK4/6i plus ET were younger (mean age 66.8 vs. 68.6, p &lt; 0.001), more likely to present with de novo MBC (p &lt; 0.001), had better performance status (50.2% vs. 40.5% patients with ECOG value 0, p = 0.001) and lower number of comorbidities (29.7% vs. 26.6% ≥ 1 comorbidity, p &lt; 0.001). Logistic regression revealed increased odds of CDK4/6i plus ET in individuals aged 50-64 (OR: 3.42, 95% CI [2.41, 4.86]) and 65-74 (OR: 3.18, 95% CI [1.68, 6.02]) versus those aged 18-49 years of age. Black individuals had lower odds of CDK4/6i plus ET (OR: 0.76, 95% CI [0.58, 1.00]) compared to White individuals. Other characteristics associated with lower odds of CDK4/6i plus ET included patients with stage III disease (OR: 0.69, 95% CI [0.52, 0.92]), lower performance status (OR: 0.50, 95% CI [0.40, 0.62]), and Medicare insurance (OR: 0.73, 95% CI [0.30, 1.78]) compared to those with commercial and Medicaid insurance. After IPW adjustment, use of CDK4/6i plus ET as 1st -line treatment was associated with significantly longer median PFS compared to ET alone (27 vs. 17 months; hazard ratio [HR] = 0.61, p &lt; 0.001). Median OS was 52 months in the CDK4/6i plus ET group and was 42 months with ET alone (HR = 0.74, p &lt; 0.001).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;In this real-world database, disparities in receiving 1st -line CDK4/6 inhibitors were seen by age, diagnosis stage, baseline performance status, comorbidity, and insurance status. In adjusted analysis, the use of 1st -line CDK4/6i plus ET yielded bett","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"144"},"PeriodicalIF":7.4,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478883","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}
引用次数: 0
Autophagy is required for mammary tumor recurrence by promoting dormant tumor cell survival following therapy. 自噬是乳腺肿瘤复发的必要条件,它能促进休眠肿瘤细胞在治疗后存活。
IF 7.4 1区 医学
Breast Cancer Research Pub Date : 2024-10-18 DOI: 10.1186/s13058-024-01878-7
Samantha Dwyer, Jason Ruth, Hans E Seidel, Amelie A Raz, Lewis A Chodosh
{"title":"Autophagy is required for mammary tumor recurrence by promoting dormant tumor cell survival following therapy.","authors":"Samantha Dwyer, Jason Ruth, Hans E Seidel, Amelie A Raz, Lewis A Chodosh","doi":"10.1186/s13058-024-01878-7","DOIUrl":"https://doi.org/10.1186/s13058-024-01878-7","url":null,"abstract":"<p><strong>Background: </strong>Mortality from breast cancer is principally due to tumor recurrence. Recurrent breast cancers arise from the pool of residual tumor cells, termed minimal residual disease, that survive treatment and may exist in a dormant state for 20 years or more following treatment of the primary tumor. As recurrent breast cancer is typically incurable, understanding the mechanisms underlying dormant tumor cell survival is a critical priority in breast cancer research. The importance of this goal is further underscored by emerging evidence suggesting that targeting dormant residual tumor cells in early-stage breast cancer patients may be a means to prevent tumor recurrence and its associated mortality. In this regard, the role of autophagy in dormant tumor cell survival and recurrence remains unresolved, with conflicting reports of both pro-survival/recurrence-promoting and pro-death/recurrence-suppressing effects of autophagy inhibition in dormant tumor cells. Resolving this question has important clinical implications.</p><p><strong>Methods: </strong>We used genetically engineered mouse models that faithfully recapitulate key features of human breast cancer progression, including minimal residual disease, tumor dormancy, and recurrence. We used genetic and pharmacological approaches to inhibit autophagy, including treatment with chloroquine, genetic knockdown of ATG5 or ATG7, or deletion of BECN and determined their effects on dormant tumor cell survival and recurrence.</p><p><strong>Results: </strong>We demonstrate that the survival and recurrence of dormant mammary tumor cells following therapy is dependent upon autophagy. We find that autophagy is induced in vivo following HER2 downregulation and remains activated in dormant residual tumor cells. Using genetic and pharmacological approaches we show that inhibiting autophagy by chloroquine administration, ATG5 or ATG7 knockdown, or deletion of a single allele of the tumor suppressor Beclin 1 is sufficient to inhibit mammary tumor recurrence, and that autophagy inhibition results in the death of dormant mammary tumor cells in vivo.</p><p><strong>Conclusions: </strong>Our findings demonstrate a pro-tumorigenic role for autophagy in tumor dormancy and recurrence following therapy, reveal that dormant tumor cells are uniquely reliant upon autophagy for their survival, and indicate that targeting dormant residual tumor cells by inhibiting autophagy impairs tumor recurrence. These studies identify a pharmacological target for a cellular state that is resistant to commonly used anti-neoplastic agents and suggest autophagy inhibition as an approach to reduce dormant minimal residual disease in order to prevent lethal tumor recurrence.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"143"},"PeriodicalIF":7.4,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478882","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}
引用次数: 0
Increasing rates of early-onset Luminal A breast cancers correlate with binge drinking patterns. 早发 Luminal A 型乳腺癌发病率的增加与酗酒模式有关。
IF 7.4 1区 医学
Breast Cancer Research Pub Date : 2024-10-18 DOI: 10.1186/s13058-024-01894-7
Jianjiu Chen, Rebecca Kehm, Wan Yang, Mary Beth Terry
{"title":"Increasing rates of early-onset Luminal A breast cancers correlate with binge drinking patterns.","authors":"Jianjiu Chen, Rebecca Kehm, Wan Yang, Mary Beth Terry","doi":"10.1186/s13058-024-01894-7","DOIUrl":"https://doi.org/10.1186/s13058-024-01894-7","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer (BC) rates have been increasing in young women in the U.S. Alcohol is an established risk factor for breast cancer and has been consistently associated with hormone receptor positive cancers, the type of breast cancer that has been increasing the fastest in young women. Given these trends, we conducted an ecological study to examine whether alcohol consumption, and specifically binge drinking trends, were correlated with female breast cancer diagnosed under 40 years of age using breast cancer data from the Surveillance, Epidemiology, and End Results (SEER) Cancer Registry. We accounted for a latent period before cancer diagnosis by using exposure 10 years before the outcome (lag model); we also conducted a separate cumulative analysis of 10-year aggregate exposure.</p><p><strong>Findings: </strong>Moderate (Incidence Rate Ratio (IRR) = 1.05, 95% Confidence Interval (CI) = 1.02-1.07) and heavy (IRR = 1.05, 95% CI = 1.02-1.07)(≥ 1 and ≥ 2 drinks/day, respectively) alcohol consumption were each associated with Luminal A breast cancer but not the other molecular subtypes. Binge drinking was associated with an increased rate of early-onset Luminal A BC in both the 10-year lag model (IRR = 1.06, 95% CI = 1.02 to 1.11) and the cumulative model (IRR = 1.05, 95% CI = 1.02-1.07). Binge drinking was also associated with early-onset Luminal B BC in the cumulative model (IRR = 1.04, 95% CI = 1.01-1.07), but not associated with ERBB2-enriched or triple negative early-onset BC in either model.</p><p><strong>Conclusion: </strong>These trends support the hypothesis that one reason for the increase in early-onset breast cancer is from increased alcohol intake including binge drinking.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"145"},"PeriodicalIF":7.4,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11487698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478897","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}
引用次数: 0
Pro-inflammatory cytokines increase temporarily after adjuvant treatment for breast cancer in postmenopausal women: a longitudinal study. 绝经后妇女接受乳腺癌辅助治疗后,促炎细胞因子会暂时增加:一项纵向研究。
IF 7.4 1区 医学
Breast Cancer Research Pub Date : 2024-10-16 DOI: 10.1186/s13058-024-01898-3
Agnes Lindholm, Marie-Louise Abrahamsen, Kristian Buch-Larsen, Djordje Marina, Michael Andersson, Jørn Wulff Helge, Peter Schwarz, Flemming Dela, Linn Gillberg
{"title":"Pro-inflammatory cytokines increase temporarily after adjuvant treatment for breast cancer in postmenopausal women: a longitudinal study.","authors":"Agnes Lindholm, Marie-Louise Abrahamsen, Kristian Buch-Larsen, Djordje Marina, Michael Andersson, Jørn Wulff Helge, Peter Schwarz, Flemming Dela, Linn Gillberg","doi":"10.1186/s13058-024-01898-3","DOIUrl":"https://doi.org/10.1186/s13058-024-01898-3","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer patients have an increased risk of cardiometabolic disease and for many patients, adjuvant therapy causes an altered lipid profile, insulin resistance and inflammation. Previous follow-up studies are inconclusive regarding the duration of therapy-induced inflammation. We examined the acute and persistent changes of adjuvant chemotherapy on inflammatory and metabolic health markers in breast cancer patients.</p><p><strong>Methods: </strong>Plasma levels of IL-6, IL-8, IL-10, IFN-γ, TNF-α, high-sensitivity C-reactive protein (hsCRP) and metabolic health parameters were analyzed before, shortly after and every six months up to two years after adjuvant chemotherapy treatment in 51 postmenopausal early breast cancer (EBC) patients, as well as in 41 healthy age- and BMI-matched controls. A target-specific multiplex assay was applied for cytokine measurements.</p><p><strong>Results: </strong>Before initiation of adjuvant therapy, plasma IL-8 levels were higher in EBC patients (31%, p = 0.0001). Also, a larger proportion of the patients had a hsCRP level above 2 mg/L (41%) compared to the controls (17%, Χ<sup>2</sup> = 5.15, p = 0.023). Plasma levels of all five cytokines, but not hsCRP, were significantly increased after compared to before adjuvant chemotherapy (15-48% increase; all p ≤ 0.05). Already six months after ending chemotherapy treatment, all plasma cytokine levels were significantly reduced and close to pre-chemotherapy levels. Adjuvant chemotherapy caused a worsened lipid profile (increased triglycerides, lower HDL levels), insulin resistance and increased plasma insulin levels that remained high during the first year after chemotherapy.</p><p><strong>Conclusion: </strong>Postmenopausal women with EBC have temporarily increased plasma levels of pro-inflammatory cytokines after adjuvant chemotherapy. Although transient, the therapy-induced increase in plasma cytokine levels, together with dyslipidemia and insulin resistance, may contribute to cardiometabolic risk in breast cancer patients treated with adjuvant chemotherapy.</p><p><strong>Trial registration: </strong>The clinical trial (registration number NCT03784651) was registered on www.</p><p><strong>Clinicaltrials: </strong>gov on 24 December 2018.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"142"},"PeriodicalIF":7.4,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478898","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}
引用次数: 0
Plasma metabolomics profiles and breast cancer risk. 血浆代谢组学特征与乳腺癌风险。
IF 7.4 1区 医学
Breast Cancer Research Pub Date : 2024-10-09 DOI: 10.1186/s13058-024-01896-5
Hui-Chen Wu, Yunjia Lai, Yuyan Liao, Maya Deyssenroth, Gary W Miller, Regina M Santella, Mary Beth Terry
{"title":"Plasma metabolomics profiles and breast cancer risk.","authors":"Hui-Chen Wu, Yunjia Lai, Yuyan Liao, Maya Deyssenroth, Gary W Miller, Regina M Santella, Mary Beth Terry","doi":"10.1186/s13058-024-01896-5","DOIUrl":"10.1186/s13058-024-01896-5","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer (BC) is the most common cancer in women and incidence rates are increasing; metabolomics may be a promising approach for identifying the drivers of the increasing trends that cannot be explained by changes in known BC risk factors.</p><p><strong>Methods: </strong>We conducted a nested case-control study (median followup 6.3 years) within the New York site of the Breast Cancer Family Registry (BCFR) (n = 40 cases and 70 age-matched controls). We conducted a metabolome-wide association study using untargeted metabolomics coupling hydrophilic interaction liquid chromatography (HILIC) and C<sub>18</sub> chromatography with high-resolution mass spectrometry (LC-HRMS) to identify BC-related metabolic features.</p><p><strong>Results: </strong>We found eight metabolic features associated with BC risk. For the four metabolites negatively associated with risk, the adjusted odds ratios (ORs) ranged from 0.31 (95% confidence interval (CI): 0.14, 0.66) (L-Histidine) to 0.65 (95% CI: 0.43, 0.98) (N-Acetylgalactosamine), and for the four metabolites positively associated with risk, ORs ranged from 1.61 (95% CI: 1.04, 2.51, (m/z: 101.5813, RT: 90.4, 1,3-dibutyl-1-nitrosourea, a potential carcinogen)) to 2.20 (95% CI: 1.15, 4.23) (11-cis-Eicosenic acid). These results were no longer statistically significant after adjusting for multiple comparisons. Adding the BC-related metabolic features to a model, including age, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk score improved the accuracy of BC prediction from an area under the curve (AUC) of 66% to 83%.</p><p><strong>Conclusions: </strong>If replicated in larger prospective cohorts, these findings offer promising new ways to identify exposures related to BC and improve BC risk prediction.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"26 1","pages":"141"},"PeriodicalIF":7.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394657","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}
引用次数: 0
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