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Overcoming doxorubicin resistance in triple-negative breast cancer using the class I-targeting HDAC inhibitor bocodepsin/OKI-179 to promote apoptosis 利用 I 类靶向 HDAC 抑制剂 bocodepsin/OKI-179 促进细胞凋亡,克服三阴性乳腺癌对多柔比星的耐药性
IF 7.4 1区 医学 Pub Date : 2024-03-01 DOI: 10.1186/s13058-024-01799-5
Stephen G. Smoots, Anna R. Schreiber, Marilyn M. Jackson, Stacey M. Bagby, Adrian T A. Dominguez, Evan D. Dus, Cameron A. Binns, Morgan MacBeth, Phaedra A. Whitty, Jennifer R. Diamond, Todd M. Pitts
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a poor prognosis. Doxorubicin is part of standard curative therapy for TNBC, but chemotherapy resistance remains an important clinical challenge. Bocodepsin (OKI-179) is a small molecule class I histone deacetylase (HDAC) inhibitor that promotes apoptosis in TNBC preclinical models. The purpose of this study was to investigate the combination of bocodepsin and doxorubicin in preclinical TNBC models and evaluate the impact on terminal cell fate, including apoptosis and senescence. TNBC cell lines were treated with doxorubicin and CellTiter-Glo was used to assess proliferation and determine doxorubicin sensitivity. Select cell lines were treated with OKI-005 (in vitro version of bocodepsin) and doxorubicin and assessed for proliferation, apoptosis as measured by Annexin V/PI, and cell cycle by flow cytometry. Immunoblotting was used to assess changes in mediators of apoptosis, cell cycle arrest, and senescence. Senescence was measured by the senescence-associated β-galactosidase assay. An MDA-MB-231 xenograft in vivo model was treated with bocodepsin, doxorubicin, or the combination and assessed for inhibition of tumor growth. shRNA knockdown of p53 was performed in the CAL-51 cell line and proliferation, apoptosis and senescence were assessed in response to combination treatment. OKI-005 and doxorubicin resulted in synergistic antiproliferative activity in TNBC cells lines regardless of p53 mutation status. The combination led to increased apoptosis and decreased senescence. In vivo, the combination resulted in increased tumor growth inhibition compared to either single agent. shRNA knock-down of p53 led to increased doxorubicin-induced senescence that was decreased with the addition of OKI-005 in vitro. The addition of bocodepsin to doxorubicin resulted in synergistic antiproliferative activity in vitro, improved tumor growth inhibition in vivo, and promotion of apoptosis which makes this a promising combination to overcome doxorubicin resistance in TNBC. Bocodepsin is currently in clinical development and has a favorable toxicity profile compared to other HDAC inhibitors supporting the feasibility of evaluating this combination in patients with TNBC.
三阴性乳腺癌(TNBC)是一种侵袭性乳腺癌亚型,预后较差。多柔比星是 TNBC 标准根治疗法的一部分,但化疗耐药性仍是一个重要的临床挑战。Bocodepsin(OKI-179)是一种小分子I类组蛋白去乙酰化酶(HDAC)抑制剂,可在TNBC临床前模型中促进细胞凋亡。本研究的目的是在TNBC临床前模型中研究bocodepsin和多柔比星的组合,并评估其对末端细胞命运(包括凋亡和衰老)的影响。用多柔比星处理 TNBC 细胞系,并使用 CellTiter-Glo 评估增殖情况和确定多柔比星的敏感性。用 OKI-005(bocodepsin 的体外版本)和多柔比星处理部分细胞系,并用流式细胞术评估细胞增殖、Annexin V/PI 测定的细胞凋亡和细胞周期。免疫印迹法用于评估细胞凋亡、细胞周期停滞和衰老介质的变化。衰老通过衰老相关的β-半乳糖苷酶检测法进行测量。用bocodepsin、多柔比星或联合疗法处理MDA-MB-231异种移植体内模型,并评估其对肿瘤生长的抑制作用。 在CAL-51细胞系中进行p53的shRNA敲除,并评估增殖、细胞凋亡和衰老对联合疗法的反应。OKI-005和多柔比星在TNBC细胞系中具有协同抗增殖活性,与p53突变状态无关。联合用药可增加细胞凋亡,减少衰老。在体内,与任何一种单药相比,联合用药都能增加对肿瘤生长的抑制作用。在多柔比星中加入波可地平,可在体外产生协同抗增殖活性,在体内改善肿瘤生长抑制,并促进细胞凋亡,这使其成为克服 TNBC 多柔比星耐药性的一种很有前景的联合疗法。Bocodepsin 目前正处于临床开发阶段,与其他 HDAC 抑制剂相比,它具有良好的毒性特征,支持在 TNBC 患者中评估这种联合用药的可行性。
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引用次数: 0
Small molecule inhibitor targeting the Hsp70-Bim protein–protein interaction in estrogen receptor-positive breast cancer overcomes tamoxifen resistance 针对雌激素受体阳性乳腺癌中 Hsp70-Bim 蛋白-蛋白相互作用的小分子抑制剂可克服他莫昔芬抗药性
IF 7.4 1区 医学 Pub Date : 2024-02-26 DOI: 10.1186/s13058-024-01790-0
Ting Song, Hong Zhang, Qicheng Zhao, Zhiyuan Hu, Ziqian Wang, Yang Song, Zhichao Zhang
Estrogen receptor (ER) positive patients compromise about 70% of breast cancers. Tamoxifen, an antagonist of ERα66 (the classic ER), is the most effective and the standard first-line drug. However, its efficacy is limited by the development of acquired resistance. A specific inhibitor of Hsp70-Bim protein–protein interaction (PPI), S1g-2, together with an inhibitor of Hsp70-Bag3 PPI, MKT-077 and an ATP-competitive inhibitor VER155008, were used as chemical tools. Cell viability assays, co-immunoprecipitation and gene knockdown were used to investigate the role of Hsp70 in tamoxifen resistance. A xenograft model was established in which tamoxifen-resistant breast cancer (MCF-7/TAM-R) cells maintained in the presence of 5 μM tamoxifen were subcutaneously inoculated. The anti-tumor efficiency of S1g-2 was measured after a daily injection of 0.8 mg/kg for 14 days. It was revealed that Hsp70-Bim PPI protects ERα-positive breast cancer from tamoxifen-induced apoptosis through binding and stabilizing ERα36, rather than ERα66, resulting in sustained EGFR mRNA and protein expression. Disruption of Hsp70-Bim PPI and downregulation of ERα36 expression in tumor samples are consistent with the in vitro functions of S1g-2, resulting in about a three-fold reduction in tumor volume. The in vivo activity and safety of S1g-2 illustrated that it is a potential strategy for Hsp70-Bim disruption to overcome tamoxifen-resistant ER-positive breast cancer.
雌激素受体(ER)阳性患者约占乳腺癌患者的 70%。他莫昔芬是ERα66(典型的ER)的拮抗剂,是最有效的标准一线药物。然而,它的疗效因获得性耐药性的产生而受到限制。研究人员使用了Hsp70-Bim蛋白-蛋白相互作用(PPI)特异性抑制剂S1g-2、Hsp70-Bag3 PPI抑制剂MKT-077和ATP竞争性抑制剂VER155008作为化学工具。细胞活力测定、共免疫沉淀和基因敲除被用来研究 Hsp70 在他莫昔芬耐药性中的作用。建立了一种异种移植模型,将他莫昔芬耐药的乳腺癌(MCF-7/TAM-R)细胞在 5 μM 他莫昔芬存在下进行皮下注射。每天注射 0.8 毫克/千克,连续注射 14 天后,测定了 S1g-2 的抗肿瘤效率。研究发现,Hsp70-Bim PPI通过结合和稳定ERα36(而非ERα66),导致表皮生长因子受体mRNA和蛋白质的持续表达,从而保护ERα阳性乳腺癌免受他莫昔芬诱导的细胞凋亡。肿瘤样本中 Hsp70-Bim PPI 的破坏和 ERα36 表达的下调与 S1g-2 的体外功能一致,从而使肿瘤体积缩小了约三倍。S1g-2的体内活性和安全性表明,它是一种潜在的Hsp70-Bim干扰策略,可用于攻克对他莫昔芬耐药的ER阳性乳腺癌。
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引用次数: 0
PTHrP intracrine actions divergently influence breast cancer growth through p27 and LIFR PTHrP 内分泌作用通过 p27 和 LIFR 对乳腺癌的生长产生不同影响
IF 7.4 1区 医学 Pub Date : 2024-02-26 DOI: 10.1186/s13058-024-01791-z
Courtney M. Edwards, Jeremy F. Kane, Jailyn A. Smith, Déja M. Grant, Jasmine A. Johnson, Maria A. Hernandez Diaz, Lawrence A. Vecchi, Kai M. Bracey, Tolu N. Omokehinde, Joseph R. Fontana, Breelyn A. Karno, Halee T. Scott, Carolina J. Vogel, Jonathan W. Lowery, T. John Martin, Rachelle W. Johnson
The role of parathyroid hormone (PTH)-related protein (PTHrP) in breast cancer remains controversial, with reports of PTHrP inhibiting or promoting primary tumor growth in preclinical studies. Here, we provide insight into these conflicting findings by assessing the role of specific biological domains of PTHrP in tumor progression through stable expression of PTHrP (-36-139aa) or truncated forms with deletion of the nuclear localization sequence (NLS) alone or in combination with the C-terminus. Although the full-length PTHrP molecule (-36-139aa) did not alter tumorigenesis, PTHrP lacking the NLS alone accelerated primary tumor growth by downregulating p27, while PTHrP lacking the NLS and C-terminus repressed tumor growth through p27 induction driven by the tumor suppressor leukemia inhibitory factor receptor (LIFR). Induction of p27 by PTHrP lacking the NLS and C-terminus persisted in bone disseminated cells, but did not prevent metastatic outgrowth, in contrast to the primary tumor site. These data suggest that the PTHrP NLS functions as a tumor suppressor, while the PTHrP C-terminus may act as an oncogenic switch to promote tumor progression through differential regulation of p27 signaling.
甲状旁腺激素(PTH)相关蛋白(PTHrP)在乳腺癌中的作用仍存在争议,临床前研究中有报道称 PTHrP 可抑制或促进原发性肿瘤生长。在这里,我们通过稳定表达 PTHrP(-36-139aa)或单独缺失核定位序列(NLS)的截断形式或结合 C 端,评估 PTHrP 的特定生物结构域在肿瘤进展中的作用,从而深入了解这些相互矛盾的研究结果。虽然全长 PTHrP 分子(-36-139aa)不会改变肿瘤的发生,但单独缺失 NLS 的 PTHrP 会通过下调 p27 来加速原发性肿瘤的生长,而缺失 NLS 和 C 端的 PTHrP 则会通过肿瘤抑制因子白血病抑制因子受体(LIFR)的 p27 诱导来抑制肿瘤的生长。缺乏 NLS 和 C 端的 PTHrP 对 p27 的诱导作用在骨播散细胞中持续存在,但并不能阻止转移生长,这与原发肿瘤部位形成鲜明对比。这些数据表明,PTHrP NLS 起着肿瘤抑制剂的作用,而 PTHrP C 端可能起着致癌开关的作用,通过对 p27 信号的不同调控来促进肿瘤的进展。
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引用次数: 0
A phase 1b study of zilovertamab in combination with paclitaxel for locally advanced/unresectable or metastatic Her2-negative breast cancer 齐洛韦坦单抗联合紫杉醇治疗局部晚期/不可切除或转移性 Her2 阴性乳腺癌的 1b 期研究
IF 7.4 1区 医学 Pub Date : 2024-02-26 DOI: 10.1186/s13058-024-01782-0
Rebecca A. Shatsky, Hemali Batra-Sharma, Teresa Helsten, Richard B. Schwab, Emily I. Pittman, Minya Pu, Elizabeth Weihe, Emanuela M. Ghia, Laura Z. Rassenti, Alfredo Molinolo, Betty Cabrera, James B. Breitmeyer, George F. Widhopf, Karen Messer, Catriona Jamieson, Thomas J. Kipps, Barbara A. Parker
Zilovertamab is a humanized monoclonal antibody targeting ROR1, an onco-embryonic antigen expressed by malignant cells of a variety of solid tumors, including breast cancer. A prior phase 1 study showed that zilovertamab was well tolerated and effective in inhibiting ROR1-signaling, which leads to activation of ERK1/2, NF-κB, and NRF2 target genes. This phase 1b study evaluated the safety and tolerability of zilovertamab with paclitaxel in patients with advanced breast cancer. Eligible patients had locally advanced, unresectable, or metastatic HER2− breast cancer with Eastern Cooperative Group performance status of 0–2 and without prior taxane therapy in the advanced setting. Study treatment included 600 mg of zilovertamab administered intravenously (IV) on Days 1 and 15 of Cycle 1 and then Day 1 of each 28-day cycle along with paclitaxel weekly at 80 mg/m2 IV. Study patients had received a median of 4 prior therapies (endocrine therapy + chemotherapy) for locally advanced, unresectable, or metastatic disease. No patient discontinued therapy due to toxicity ascribed to zilovertamab. Adverse events were consistent with the known safety profile of paclitaxel. Of 16 patients, 6 (38%) had a partial response, and 6/16 (38%) patients had stable disease as best tumor response. The combination of zilovertamab and paclitaxel was safe and well tolerated in heavily pre-treated advanced breast cancer patients. Further evaluation of ROR1 targeting in breast cancer patients with zilovertamab is warranted. Trial Registration: NCT02776917. Registered on ClinicalTrials.gov on 05/17/2016.
Zilovertamab是一种靶向ROR1的人源化单克隆抗体,ROR1是包括乳腺癌在内的多种实体瘤恶性细胞表达的一种肿瘤胚胎抗原。之前的一项1期研究表明,zilovertamab耐受性良好,能有效抑制ROR1信号传导,从而激活ERK1/2、NF-κB和NRF2靶基因。这项1b期研究评估了zilovertamab联合紫杉醇治疗晚期乳腺癌患者的安全性和耐受性。符合条件的患者均为局部晚期、无法切除或转移性 HER2-乳腺癌,东方合作组表现状态为 0-2,且既往未接受过晚期紫杉类药物治疗。研究治疗包括在第1周期的第1天和第15天静脉注射600毫克齐洛韦他单抗,然后在每个28天周期的第1天静脉注射紫杉醇,每周静脉注射80毫克/平方米。研究患者此前曾接受过中位数为4次的局部晚期、不可切除或转移性疾病治疗(内分泌治疗+化疗)。没有患者因齐洛韦坦单抗引起的毒性而中断治疗。不良反应与已知的紫杉醇安全性相符。在16名患者中,6名(38%)患者有部分反应,6/16(38%)患者的最佳肿瘤反应是病情稳定。在接受过大量预处理的晚期乳腺癌患者中,zilovertamab和紫杉醇的联合用药安全且耐受性良好。有必要进一步评估使用齐洛韦坦单抗对乳腺癌患者进行ROR1靶向治疗的效果。试验注册:NCT02776917。2016年5月17日在ClinicalTrials.gov上注册。
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引用次数: 0
The prostate-specific membrane antigen holds potential as a vascular target for endogenous radiotherapy with [177Lu]Lu-PSMA-I&T for triple-negative breast cancer 前列腺特异性膜抗原有望成为使用[177Lu]Lu-PSMA-I&T 对三阴性乳腺癌进行内源性放射治疗的血管靶点
IF 7.4 1区 医学 Pub Date : 2024-02-20 DOI: 10.1186/s13058-024-01787-9
Amelie Heesch, Alexandru Florea, Jochen Maurer, Pardes Habib, Laura S. Werth, Thomas Hansen, Elmar Stickeler, Sabri E. M. Sahnoun, Felix M. Mottaghy, Agnieszka Morgenroth
Overexpression of prostate-specific membrane antigen (PSMA) on the vasculature of triple-negative breast cancer (TNBC) presents a promising avenue for targeted endogenous radiotherapy with [177Lu]Lu-PSMA-I&T. This study aimed to assess and compare the therapeutic efficacy of a single dose with a fractionated dose of [177Lu]Lu-PSMA-I&T in an orthotopic model of TNBC. Rj:NMRI-Foxn1nu/nu mice were used as recipients of MDA-MB-231 xenografts. The single dose group was treated with 1 × 60 ± 5 MBq dose of [177Lu]Lu-PSMA-I&T, while the fractionated dose group received 4 × a 15 ± 2 MBq dose of [177Lu]Lu-PSMA-I&T at 7 day intervals. The control group received 0.9% NaCl. Tumor progression was monitored using [18F]FDG-PET/CT. Ex vivo analysis encompassed immunostaining, TUNEL staining, H&E staining, microautoradiography, and autoradiography. Tumor volumes were significantly smaller in the single dose (p < 0.001) and fractionated dose (p < 0.001) groups. Tumor growth inhibition rates were 38% (single dose) and 30% (fractionated dose). Median survival was notably prolonged in the treated groups compared to the control groups (31d, 28d and 19d for single dose, fractionated dose and control, respectively). [177Lu]Lu-PSMA-I&T decreased the size of viable tumor areas. We further demonstrated, that [177Lu]Lu-PSMA-I&T binds specifically to the tumor-associated vasculature. This study highlights the potential of [177Lu]Lu-PSMA-I&T for endogenous radiotherapy of TNBC.
前列腺特异性膜抗原(PSMA)在三阴性乳腺癌(TNBC)血管上的过度表达为使用[177Lu]Lu-PSMA-I&T进行靶向内放射治疗提供了一个前景广阔的途径。本研究旨在评估和比较单剂量与分剂量[177Lu]Lu-PSMA-I&T在TNBC正位模型中的疗效。Rj:NMRI-Foxn1nu/nu小鼠是MDA-MB-231异种移植物的受体。单剂量组接受1 × 60 ± 5 MBq剂量的[177Lu]Lu-PSMA-I&T治疗,分剂量组接受4 × 15 ± 2 MBq剂量的[177Lu]Lu-PSMA-I&T治疗,间隔7天。对照组接受 0.9% NaCl。使用[18F]FDG-PET/CT监测肿瘤进展。体内外分析包括免疫染色、TUNEL染色、H&E染色、显微自动放射摄影和自动放射摄影。单剂量组(p < 0.001)和分剂量组(p < 0.001)的肿瘤体积明显较小。肿瘤生长抑制率分别为 38%(单剂量)和 30%(分次剂量)。与对照组相比,治疗组的中位生存期明显延长(单剂量组、分剂量组和对照组的中位生存期分别为31天、28天和19天)。[177Lu]Lu-PSMA-I&T能缩小存活肿瘤区域的大小。我们进一步证实,[177Lu]Lu-PSMA-I&T 能与肿瘤相关血管特异性结合。这项研究凸显了[177Lu]Lu-PSMA-I&T在TNBC内源性放射治疗中的潜力。
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引用次数: 0
Improving lesion detection in mammograms by leveraging a Cycle-GAN-based lesion remover 利用基于 Cycle-GAN 的病灶清除器改进乳腺 X 光检查中的病灶检测
IF 7.4 1区 医学 Pub Date : 2024-02-01 DOI: 10.1186/s13058-024-01777-x
Juhun Lee, Robert M. Nishikawa
The wide heterogeneity in the appearance of breast lesions and normal breast structures can confuse computerized detection algorithms. Our purpose was therefore to develop a Lesion Highlighter (LH) that can improve the performance of computer-aided detection algorithms for detecting breast cancer on screening mammograms. We hypothesized that a Cycle-GAN based Lesion Remover (LR) could act as an LH, which can improve the performance of lesion detection algorithms. We used 10,310 screening mammograms from 4,832 women that included 4,942 recalled lesions (BI-RADS 0) and 5,368 normal results (BI-RADS 1). We divided the dataset into Train:Validate:Test folds with the ratios of 0.64:0.16:0.2. We segmented image patches (400 × 400 pixels) from either lesions marked by MQSA radiologists or normal tissue in mammograms. We trained a Cycle-GAN to develop two GANs, where each GAN transferred the style of one image to another. We refer to the GAN transferring the style of a lesion to normal breast tissue as the LR. We then highlighted the lesion by color-fusing the mammogram after applying the LR to its original. Using ResNet18, DenseNet201, EfficientNetV2, and Vision Transformer as backbone architectures, we trained three deep networks for each architecture, one trained on lesion highlighted mammograms (Highlighted), another trained on the original mammograms (Baseline), and Highlighted and Baseline combined (Combined). We conducted ROC analysis for the three versions of each deep network on the test set. The Combined version of all networks achieved AUCs ranging from 0.963 to 0.974 for identifying the image with a recalled lesion from a normal breast tissue image, which was statistically improved (p-value < 0.001) over their Baseline versions with AUCs that ranged from 0.914 to 0.967. Our results showed that a Cycle-GAN based LR is effective for enhancing lesion conspicuity and this can improve the performance of a detection algorithm.
乳腺病变和正常乳腺结构的外观差异很大,会使计算机检测算法感到困惑。因此,我们的目的是开发一种病灶高亮器(LH),以提高计算机辅助检测算法的性能,从而在乳房X光筛查中检测出乳腺癌。我们假设,基于循环-广义聚类分析的病变去除器(LR)可以充当病变高亮器,从而提高病变检测算法的性能。我们使用了来自 4832 名女性的 10,310 张筛查乳房 X 光照片,其中包括 4,942 个召回病灶(BI-RADS 0)和 5,368 个正常结果(BI-RADS 1)。我们将数据集按 0.64:0.16:0.2 的比例分为训练:验证:测试褶皱。我们从 MQSA 放射科医生标记的病灶或乳房 X 光照片中的正常组织中分割出图像片段(400 × 400 像素)。我们训练了一个 Cycle-GAN 来开发两个 GAN,其中每个 GAN 将一个图像的样式转移到另一个图像上。我们将将病变风格转移到正常乳腺组织的 GAN 称为 LR。然后,我们将 LR 应用于原始乳房图像后,通过颜色融合乳房图像来突出病变。我们使用 ResNet18、DenseNet201、EfficientNetV2 和 Vision Transformer 作为骨干架构,为每个架构训练了三个深度网络,其中一个是针对病变高亮乳房 X 光照片(高亮)训练的,另一个是针对原始乳房 X 光照片(基线)训练的,还有一个是高亮和基线组合(组合)训练的。我们在测试集上对每个深度网络的三个版本进行了 ROC 分析。所有网络的组合版本在从正常乳腺组织图像中识别出有召回病灶的图像方面取得了 0.963 到 0.974 不等的 AUC 值,与它们的基线版本(AUC 值在 0.914 到 0.967 之间)相比,在统计学上有所改进(p 值 < 0.001)。我们的研究结果表明,基于 Cycle-GAN 的 LR 能有效增强病变的清晰度,从而提高检测算法的性能。
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引用次数: 0
TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer TBCRC 039:术前服用或不服用紫杉醇治疗三阴性炎性乳腺癌的鲁索利替尼 II 期研究
IF 7.4 1区 医学 Pub Date : 2024-01-31 DOI: 10.1186/s13058-024-01774-0
Filipa Lynce, Laura E. Stevens, Zheqi Li, Jane E. Brock, Anushree Gulvady, Ying Huang, Faina Nakhlis, Ashka Patel, Jeremy M. Force, Tufia C. Haddad, Naoto Ueno, Vered Stearns, Antonio C. Wolff, Amy S. Clark, Jennifer R. Bellon, Edward T. Richardson, Justin M. Balko, Ian E. Krop, Eric P. Winer, Paulina Lange, E. Shelley Hwang, Tari A. King, Sara M. Tolaney, Alastair Thompson, Gaorav P. Gupta, Elizabeth A. Mittendorf, Meredith M. Regan, Beth Overmoyer, Kornelia Polyak
Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC. We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR). Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB+ T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells. In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target. www.clinicaltrials.gov , NCT02876302. Registered 23 August 2016.
炎性乳腺癌(IBC)患者的总体临床预后较差,其中三阴性 IBC(TN-IBC)患者的生存率最差,因此需要研究新型疗法。临床前研究表明,JAK1/2抑制剂鲁索利替尼(RUX)可能是治疗TN-IBC的有效疗法。我们开展了一项针对 TN-IBC 的嵌套机会窗随机 II 期研究。未经治疗的患者接受了单用 RUX 或 RUX 加紫杉醇 (PAC) 的 7 天磨合。磨合期结束后,单用 RUX 的患者接受为期 12 周的 RUX + PAC 或单用 PAC 新辅助治疗;接受 RUX + PAC 治疗的患者继续接受为期 12 周的治疗。随后,所有患者都在手术前接受了4个周期的多柔比星加环磷酰胺治疗。在基线(磨合前)和磨合期治疗后进行肿瘤活检研究。通过免疫染色法评估肿瘤的磷酸化STAT3(pSTAT3),并通过RNA-seq分析肿瘤子集。主要终点是pSTAT3阳性肿瘤中pSTAT3阴性肿瘤的百分比。次要终点包括病理完全反应(pCR)。共有 23 名患者入组,其中 21 人完成了术前治疗。在RUX治疗后的活检样本中,pSTAT3和IL-6/JAK/STAT3信号转导下降,而与单用RUX相比,RUX+PAC的持续治疗可上调IL-6/JAK/STAT3信号转导。两种治疗方法都会减少 GZMB+ T 细胞,这意味着免疫抑制。单独使用 RUX 可有效抑制 JAK/STAT3 信号传导,但与 PAC 联合使用则抑制不完全。RUX 单独或联合使用的免疫抑制作用可能会抵消其对癌细胞生长的抑制作用。总之,在 TN-IBC 中使用 RUX 与 pSTAT3 水平下降有关,尽管没有临床益处。要进一步评估作为癌症治疗靶点的JAK2/STAT3信号转导,可能需要针对癌细胞的JAK2/STAT3靶点或与免疫疗法相结合。www.clinicaltrials.gov ,NCT02876302。2016年8月23日注册。
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引用次数: 0
Increased risk of contralateral breast cancer for BRCA1/2 wild-type, high-risk Korean breast cancer patients: a retrospective cohort study BRCA1/2 野生型高危韩国乳腺癌患者罹患对侧乳腺癌的风险增加:一项回顾性队列研究
IF 7.4 1区 医学 Pub Date : 2024-01-22 DOI: 10.1186/s13058-024-01769-x
Eunhye Kang, Ji-Jung Jung, Changjin Lim, Hong-Kyu Kim, Han-Byoel Lee, Wonshik Han, Hyeong-Gon Moon
This study aimed to investigate the contralateral breast cancer (CBC) recurrence rate in Korean breast cancer patients according to their BRCA1/2 germline mutation status, focusing particularly on the CBC recurrence risk in BRCA1/2 negative (BRCAx) patients. We conducted a retrospective study on 13,107 primary breast cancer patients. The patients were divided into high-risk and low-risk groups for hereditary breast cancer based on the Korean National Health Insurance Service’s eligibility criteria for BRCA1/2 germline mutation testing. The high-risk group was further categorized into the BRCA mutation group, the BRCAx group, and the not tested group. We evaluated the overall survival and cumulative risk of developing CBC in these patients. Among 4494 high-risk patients, 973 (21.7%) underwent genetic testing for BRCA1/2 germline mutation, revealing mutations in 158 patients (16.2%). We observed significant overall survival differences across all four groups, with the high-risk, not-tested group demonstrating notably worse overall survival (p < 0.001). However, when adjusted for other prognostic factors, there was no significant differences in hazard ratio of death between the four groups. The cumulative risk of CBC also varied among the groups. Patients with BRCA1/2 mutations showed a 7.3-fold increased risk of CBC compared to the low-risk group (95% CI 4.11–13.0, p < 0.001). Interestingly, BRCAx patients also demonstrated a significantly higher risk of CBC (HR 2.77, 95% CI 1.76–4.35, p < 0.001). The prognostic importance of the BRCAx for CBC recurrence persisted after adjusting for the age and subtype, but became insignificant when the family history of breast cancer was adjusted. Breast cancer patients who are at high risk of hereditary breast cancer but with wild-type BRCA 1/2 genes (BRCAx) have increased risk of developing contralateral breast cancer when compared to the low-risk patients. More careful surveillance and follow-up can be offered to these patients especially when they have family history of breast cancer.
本研究旨在根据 BRCA1/2 基因突变状态调查韩国乳腺癌患者的对侧乳腺癌(CBC)复发率,尤其关注 BRCA1/2 阴性(BRCAx)患者的 CBC 复发风险。我们对 13107 名原发性乳腺癌患者进行了回顾性研究。根据韩国国民健康保险服务局的 BRCA1/2 基因突变检测资格标准,这些患者被分为遗传性乳腺癌的高风险组和低风险组。高风险组又分为 BRCA 基因突变组、BRCAx 组和未检测组。我们评估了这些患者的总生存率和罹患 CBC 的累积风险。在 4494 名高风险患者中,有 973 人(21.7%)接受了 BRCA1/2 基因突变的基因检测,其中有 158 人(16.2%)发现了基因突变。我们观察到所有四组患者的总生存率存在明显差异,其中未接受检测的高风险组患者的总生存率明显较低(P < 0.001)。然而,在对其他预后因素进行调整后,四组患者的死亡危险比没有明显差异。CBC 的累积风险在各组之间也存在差异。与低风险组相比,BRCA1/2 基因突变患者的 CBC 风险增加了 7.3 倍(95% CI 4.11-13.0,p < 0.001)。有趣的是,BRCAx 患者的 CBC 风险也明显更高(HR 2.77,95% CI 1.76-4.35,p <0.001)。在对年龄和亚型进行调整后,BRCAx 对 CBC 复发的预后重要性依然存在,但在对乳腺癌家族史进行调整后,其重要性变得不明显。与低风险患者相比,遗传性乳腺癌高风险但具有野生型 BRCA 1/2 基因(BRCAx)的乳腺癌患者罹患对侧乳腺癌的风险更高。对这些患者,尤其是有乳腺癌家族史的患者,可以进行更仔细的监测和随访。
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引用次数: 0
Differential patterns of reproductive and lifestyle risk factors for breast cancer according to birth cohorts among women in China, Japan and Korea 中国、日本和韩国妇女不同出生组群的乳腺癌生殖和生活方式风险因素的差异模式
IF 7.4 1区 医学 Pub Date : 2024-01-22 DOI: 10.1186/s13058-024-01766-0
Salma Nabila, Ji-Yeob Choi, Sarah Krull Abe, Md Rashedul Islam, Md Shafiur Rahman, Eiko Saito, Aesun Shin, Melissa A. Merritt, Ryoko Katagiri, Xiao-Ou Shu, Norie Sawada, Akiko Tamakoshi, Ritsu Sakata, Atsushi Hozawa, Jeongseon Kim, Chisato Nagata, Sue K. Park, Sun-Seog Kweon, Hui Cai, Shoichiro Tsugane, Takashi Kimura, Seiki Kanemura, Yumi Sugawara, Keiko Wada, Min-Ho Shin, Habibul Ahsan, Paolo Boffetta, Kee Seng Chia, Keitaro Matsuo, You-Lin Qiao, Nathaniel Rothman, Wei Zheng, Manami Inoue, Daehee Kang
The birth cohort effect has been suggested to influence the rate of breast cancer incidence and the trends of associated reproductive and lifestyle factors. We conducted a cohort study to determine whether a differential pattern of associations exists between certain factors and breast cancer risk based on birth cohorts. This was a cohort study using pooled data from 12 cohort studies. We analysed associations between reproductive (menarche age, menopause age, parity and age at first delivery) and lifestyle (smoking and alcohol consumption) factors and breast cancer risk. We obtained hazard ratios (HRs) with 95% confidence intervals (CIs) using the Cox proportional hazard regression analysis on the 1920s, 1930s, 1940s and 1950s birth cohorts. Parity was found to lower the risk of breast cancer in the older but not in the younger birth cohort, whereas lifestyle factors showed associations with breast cancer risk only among the participants born in the 1950s. In the younger birth cohort group, the effect size was lower for parous women compared to the other cohort groups (HR [95% CI] 0.86 [0.66–1.13] compared to 0.60 [0.49–0.73], 0.46 [0.38–0.56] and 0.62 [0.51–0.77]). Meanwhile, a higher effect size was found for smoking (1.45 [1.14–1.84] compared to 1.25 [0.99–1.58], 1.06 [0.85–1.32] and 0.86 [0.69–1.08]) and alcohol consumption (1.22 [1.01–1.48] compared to 1.10 [0.90–1.33], 1.15 [0.96–1.38], and 1.07 [0.91–1.26]). We observed different associations of parity, smoking and alcohol consumption with breast cancer risk across various birth cohorts.
出生队列效应被认为会影响乳腺癌的发病率以及相关生殖和生活方式因素的变化趋势。我们进行了一项队列研究,以确定某些因素与乳腺癌风险之间是否存在基于出生队列的不同关联模式。这是一项队列研究,使用了 12 项队列研究的汇总数据。我们分析了生殖因素(初潮年龄、绝经年龄、胎次和初产年龄)和生活方式因素(吸烟和饮酒)与乳腺癌风险之间的关系。我们对 20 世纪 20 年代、30 年代、40 年代和 50 年代的出生队列进行了 Cox 比例危险回归分析,得出了危险比 (HRs) 和 95% 置信区间 (CIs)。研究发现,在年龄较大的出生组群中,胎次可降低乳腺癌风险,但在年龄较小的出生组群中,胎次并不能降低乳腺癌风险,而生活方式因素只与 20 世纪 50 年代出生的参与者的乳腺癌风险有关。在较年轻的出生队列组中,与其他队列组相比,准妈妈的效应大小较低(HR [95% CI] 0.86 [0.66-1.13],而其他队列组为 0.60 [0.49-0.73]、0.46 [0.38-0.56] 和 0.62 [0.51-0.77])。同时,吸烟(1.45 [1.14-1.84] 比 1.25 [0.99-1.58]、1.06 [0.85-1.32] 和 0.86 [0.69-1.08])和饮酒(1.22 [1.01-1.48] 比 1.10 [0.90-1.33]、1.15 [0.96-1.38] 和 1.07 [0.91-1.26])的效应大小更高。我们观察到,在不同的出生组群中,孕妇的奇偶性、吸烟和饮酒与乳腺癌风险之间存在不同的关系。
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引用次数: 0
Evidence of steady-state fibroblast subtypes in the normal human breast as cells-of-origin for perturbed-state fibroblasts in breast cancer 证明正常人乳房中的稳态成纤维细胞亚型是乳腺癌中扰动态成纤维细胞的起源细胞
IF 7.4 1区 医学 Pub Date : 2024-01-16 DOI: 10.1186/s13058-024-01763-3
Mikkel Morsing Bagger, Jonas Sjölund, Jiyoung Kim, Katharina Theresa Kohler, René Villadsen, Abbas Jafari, Moustapha Kassem, Kristian Pietras, Lone Rønnov-Jessen, Ole William Petersen
Human breast cancer most frequently originates within a well-defined anatomical structure referred to as the terminal duct lobular unit (TDLU). This structure is endowed with its very own lobular fibroblasts representing one out of two steady-state fibroblast subtypes—the other being interlobular fibroblasts. While cancer-associated fibroblasts (CAFs) are increasingly appreciated as covering a spectrum of perturbed states, we lack a coherent understanding of their relationship—if any—with the steady-state fibroblast subtypes. To address this, we here established two autologous CAF lines representing inflammatory CAFs (iCAFs) and myofibroblast CAFs (myCAFs) and compared them with already established interlobular- and lobular fibroblasts with respect to their origin and impact on tumor formation. Primary breast tumor-derived CAFs were transduced to express human telomerase reverse transcriptase (hTERT) and sorted into CD105low and CD105high populations using fluorescence-activated cell sorting (FACS). The two populations were tested for differentiation similarities to iCAF and myCAF states through transcriptome-wide RNA-Sequencing (RNA-Seq) including comparison to an available iCAF-myCAF cell state atlas. Inference of origin in interlobular and lobular fibroblasts relied on RNA-Seq profiles, immunocytochemistry and growth characteristics. Osteogenic differentiation and bone formation assays in culture and in vivo were employed to gauge for origin in bone marrow-derived mesenchymal stem cells (bMSCs). Functional characteristics were assessed with respect to contractility in culture and interaction with tumor cells in mouse xenografts. The cells’ gene expression signatures were tested for association with clinical outcome of breast cancer patients using survival data from The Cancer Genome Atlas database. We demonstrate that iCAFs have properties in common with interlobular fibroblasts while myCAFs and lobular fibroblasts are related. None of the CAFs qualify as bMSCs as revealed by lack of critical performance in bone formation assays. Functionally, myCAFs and lobular fibroblasts are almost equally tumor promoting as opposed to iCAFs and interlobular fibroblasts. A myCAF gene signature is found to associate with poor breast cancer-specific survival. We propose that iCAFs and myCAFs originate in interlobular and lobular fibroblasts, respectively, and more importantly, that the tumor-promoting properties of lobular fibroblasts render the TDLU an epicenter for breast cancer evolution.
人类乳腺癌最常起源于一个定义明确的解剖结构,即末端导管小叶单元(TDLU)。这种结构具有自己的小叶成纤维细胞,是两种稳态成纤维细胞亚型中的一种,另一种是小叶间成纤维细胞。尽管人们越来越认识到癌症相关成纤维细胞(CAFs)涵盖了一系列紊乱状态,但我们对它们与稳态成纤维细胞亚型之间的关系缺乏一致的认识。为了解决这个问题,我们在这里建立了两个自体CAF品系,分别代表炎性CAFs(iCAFs)和肌成纤维细胞CAFs(myCAFs),并就它们的来源和对肿瘤形成的影响与已经建立的小叶间成纤维细胞和小叶成纤维细胞进行了比较。原发性乳腺肿瘤来源的 CAFs 经转导后表达人端粒酶逆转录酶(hTERT),并使用荧光激活细胞分拣(FACS)技术将其分拣为 CD105 低和 CD105 高两种群体。通过全转录组RNA测序(RNA-Seq),包括与现有的iCAF-myCAF细胞状态图谱进行比较,检测这两个群体与iCAF和myCAF状态的分化相似性。根据 RNA-Seq 图谱、免疫细胞化学和生长特征推断球间和小叶成纤维细胞的起源。骨髓间充质干细胞(bMSCs)采用了培养和体内成骨分化和骨形成试验来判断来源。对培养过程中的收缩性以及在小鼠异种移植中与肿瘤细胞相互作用的功能特性进行了评估。利用癌症基因组图谱数据库中的生存数据,测试了细胞的基因表达特征与乳腺癌患者临床结果的关联。我们证明,iCAFs 与小叶间成纤维细胞具有共同特性,而 myCAFs 与小叶成纤维细胞具有相关性。由于在骨形成试验中缺乏关键性能,因此没有一种 CAFs 符合 bMSCs 的条件。在功能上,myCAFs 和小叶成纤维细胞与 iCAFs 和小叶间成纤维细胞相比,几乎同样具有肿瘤促进作用。研究发现,myCAF基因特征与乳腺癌特异性生存率低有关。我们认为,iCAFs 和 myCAFs 分别起源于小叶间成纤维细胞和小叶成纤维细胞,更重要的是,小叶成纤维细胞的肿瘤促进特性使 TDLU 成为乳腺癌演变的中心。
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引用次数: 0
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Breast Cancer Research
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