乳腺癌中 MMP9 表达升高是患者生存期较短的预测因子。
- 作者列表："Joseph C","Alsaleem M","Orah N","Narasimha PL","Miligy IM","Kurozumi S","Ellis IO","Mongan NP","Green AR","Rakha EA
PURPOSE:MMP9 is a matricellular protein associated with extracellular matrix (ECM) remodelling, that promotes tumour progression, and modulates the activity of cell adhesion molecules and cytokines. This study aims to assess the prognostic value of MMP9 and its association with cytoskeletal modulators in early-stage invasive breast cancer (BC). METHODS:MMP9 expression was evaluated by immunohistochemistry using a well-characterised series of primary BC patients with long-term clinical follow-up. Association with clinicopathological factors, patient outcome and ECM remodelling BC-biomarkers were investigated. METABRIC dataset, BC-GenExMiner v4.0 and TCGA were used for the external validation of MMP9 expression. GSEA gene enrichment analyses were used to evaluate MMP9 associated pathways. RESULTS:MMP9 immunopositivity was observed in the stroma and cytoplasm of BC cells. Elevated MMP9 protein levels were associated with high tumour grade, high Nottingham Prognostic Index, and hormonal receptor negativity. Elevated MMP9 protein expression correlated significantly with cytokeratin 17 (Ck17), Epidermal Growth Factor Receptor (EGFR), proliferation (Ki67) biomarkers, cell surface adhesion receptor (CD44) and cell division control protein 42 (CDC42). Cytoplasmic MMP9 expression was an independent prognostic factor associated with shorter BC-specific survival. In the external validation cohorts, MMP9 expression was also associated with poor patients' outcome. Transcriptomic analysis confirmed a positive association between MMP9 and ECM remodelling biomarkers. GSEA analysis supports MMP9 association with ECM and cytoskeletal pathways. CONCLUSION:This study provides evidence for the prognostic value of MMP9 in BC. Further functional studies to decipher the role of MMP9 and its association with cytoskeletal modulators in BC progression are warranted.
目的: MMP9 是一种与细胞外基质 (ECM) 重塑相关的基质细胞蛋白，可促进肿瘤进展，并调节细胞粘附分子和细胞因子的活性。本研究旨在评估 MMP9 在早期浸润性乳腺癌 (BC) 中的预后价值及其与细胞骨架调节剂的相关性。 方法: 通过免疫组织化学方法评价 MMP9 的表达，使用具有良好特征的原发性 BC 患者系列，并进行长期临床随访。研究了与临床病理因素、患者结局和 ECM 重塑 BC-生物标志物的相关性。METABRIC 数据集、 BC-GenExMiner v4.0 和 TCGA 用于 MMP9 表达的外部验证。使用 GSEA 基因富集分析评价 MMP9 相关通路。 结果: MMP9 在 BC 细胞的间质和胞浆中呈免疫阳性表达。MMP9 蛋白水平升高与高肿瘤分级、高诺丁汉预后指数和激素受体阴性相关。MMP9 蛋白表达升高与细胞角蛋白 17 (Ck17) 、表皮生长因子受体 (EGFR) 、增殖 (Ki67) 生物标志物、细胞表面粘附受体 (CD44) 显著相关和细胞分裂控制蛋白 42 (CDC42)。细胞质 MMP9 表达是与较短的 BC 特异性生存相关的独立预后因素。在外部验证队列中，MMP9 表达也与患者不良结局相关。转录组学分析证实 MMP9 和 ECM 重塑生物标志物之间呈正相关。GSEA 分析支持 MMP9 与 ECM 和细胞骨架通路的关联。 结论: 本研究为 MMP9 在 BC 中的预后价值提供了证据。需要进一步的功能研究来破译 MMP9 的作用及其与细胞骨架调节剂在 BC 进展中的关联。
METHODS::The emerging significance of the bitter taste receptors (T2Rs) role in the extraoral tissues alludes to their potential role in many pathophysiological conditions. The dysregulation of T2R expression and function in disease conditions has now been demonstrated in airways diseases, neurological disorders, and in some cancers. However, the role of T2Rs in the pathophysiology of breast cancer is unexplored thus far. Previously, we demonstrated differential expression of the 25 T2Rs in breast cancer (BC) cells. Based on our previous findings we selected two T2Rs, T2R4 and T2R14 for this work. The objective of the current study is to investigate the expression of T2R4 and T2R14 in BC clinical samples and to examine their physiological role using highly metastatic BC and non-cancerous cell lines. Using approaches, which involve receptor knockdown, pharmacological activation and biochemical assays we report that (i) T2R4 and T2R14 expression patterns are dissimilar, with decreased levels of T2R4 and increased levels of T2R14 in BC clinical samples compared to non-cancerous controls. (ii) Activation of T2Rs with their respective agonist elicited physiological responses in metastatic breast cancer cells, and no responses were seen in non-tumorigenic breast epithelial cells. (iii) Agonist activation of T2Rs (irrespective of T2R subtype) induced anti-proliferative, pro-apoptotic, and anti-migratory responses in highly metastatic breast cancer cells. Taken together, our findings demonstrate that the chemosensory T2R signaling network is involved in evoking physiological responses in the metastatic breast cancer cell line.
METHODS::RAD50 is commonly depleted in basal-like breast cancer with concomitant absence of INPP4B and several tumor suppressors such as BRCA1 and TP53. Our previous study revealed that INPP4B and RAD50 interact and such an interaction is associated with breast cancer survival at the transcriptional, translational and genomic levels. In the present study, we explored single nucleotide polymorphisms (SNPs) of these two genes that have synergistic effects on breast cancer survival to decipher mechanisms driving their interactions at the genetic level. The Cox's proportional hazards model was used to test whether SNPs of these two genes are interactively associated with breast cancer survival, following expression quantitative trait loci (eQTL) analysis and functional investigations. Our study revealed two disease-associating blocks, each encompassing five and two non-linkage disequilibrium linked SNPs of INPP4B and RAD50, respectively. Concomitant presence of any rare homozygote from each disease-associating block is synergistically prognostic of poor breast cancer survival. Such synergy is mediated via bypassing pathways controlling cell proliferation and DNA damage repair, which are represented by INPP4B and RAD50. Our study provided genetic evidence of interactions between INPP4B and RAD50, and deepened our understandings on the orchestrated genetic machinery governing tumor progression.
METHODS:BACKGROUND:Increased usage of genomic risk assessment assays suggests increased reliance on data provided by these assays to guide therapy decisions. The current study aimed to assess the change in treatment decision and physician confidence based on the 70-gene risk of recurrence signature (70-GS, MammaPrint) and the 80-gene molecular subtype signature (80-GS, BluePrint) in early stage breast cancer patients. METHODS:IMPACt, a prospective, case-only study, enrolled 452 patients between November 2015 and August 2017. The primary objective population included 358 patients with stage I-II, hormone receptor-positive, HER2-negative breast cancer. The recommended treatment plan and physician confidence were captured before and after receiving results for 70-GS and 80-GS. Treatment was started after obtaining results. The distribution of 70-GS High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to the distribution of 80-GS compared to IHC status. RESULTS:The 70-GS classified 62.5% (n = 224/358) of patients as LR and 37.5% (n = 134/358) as HR. Treatment decisions were changed for 24.0% (n = 86/358) of patients after receiving 70-GS and 80-GS results. Of the LR patients initially prescribed CT, 71.0% (44/62) had CT removed from their treatment recommendation. Of the HR patients not initially prescribed CT, 65.1% (41/63) had CT added. After receiving 70-GS results, CT was included in 83.6% (n = 112/134) of 70-GS HR patient treatment plans, and 91.5% (n = 205/224) of 70-GS LR patient treatment plans did not include CT. For patients who disagreed with the treatment recommended by their physicians, most (94.1%, n = 16/17) elected not to receive CT when it was recommended. For patients whose physician-recommended treatment plan was discordant with 70-GS results, discordance was significantly associated with age and lymph node status. CONCLUSIONS:The IMPACt trial showed that treatment plans were 88.5% (n = 317/358) in agreement with 70-GS results, indicating that physicians make treatment decisions in clinical practice based on the 70-GS result. In clinically high risk, 70-GS Low Risk patients, there was a 60.0% reduction in treatment recommendations that include CT. Additionally, physicians reported having greater confidence in treatment decisions for their patients in 72% (n = 258/358) of cases after receiving 70-GS results. TRIAL REGISTRATION:"Measuring the Impact of MammaPrint on Adjuvant and Neoadjuvant Treatment in Breast Cancer Patients: A Prospective Registry" (NCT02670577) retrospectively registered on Jan 27, 2016.