PO.PR01.03 · 预防研究
致密乳腺组织中作为乳腺癌发生潜在驱动因素的独特分子特征
Distinct molecular signatures in dense breast tissue as potential drivers of breast cancer development
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
乳腺密度是乳腺癌一个重要的独立危险因素；与非致密型乳腺的女性相比，致密型乳腺的女性罹患该疾病的风险增加4-6倍。有观点认为，所有乳腺癌病例中有30%发生于致密区域>50%的女性。乳腺密度反映了乳腺组织构成的差异。其特征为高比例的间质，含有胶原蛋白及其他ECM蛋白、成纤维细胞、内皮细胞和免疫细胞，提示一种促肿瘤的炎症微环境。为研究致密与非致密乳腺组织之间的分子差异及其与三阴性乳腺癌（TNBC）的关联，我们使用PanCancer IO 360 panel探究了各样本间的RNA表达和信号通路调控。我们观察到受试者间RNA表达的差异，从而识别出致密乳腺中不同的分子群组。受试者被聚类为3种具有独特分子特征和生物学通路的亚型。我们识别出一个群组（G1），其参与炎症过程的基因表达增加，但仍与非致密乳腺的表型保持较密切的关联。我们还识别出另外两个群组（G2和G3），它们相对于非致密组更为独特，且彼此不同。这些群组分别与微环境中的重组和细胞结构（G2）以及增殖调控、癌症通路和肿瘤发生中基因表达增加（G3）相关。在此初步筛查中，这些群组似乎与年龄或绝经阶段无关；相反，它们更像是密度的亚型或密度发展的阶段。此外，通过分析TNBC样本中的RNA表达，我们发现其与致密G3样本相关，后者表达更多与DNA修复相关的RNA，并伴有DNA损伤、表观遗传调控、凋亡和代谢应激通路的上调。与此同时，诸如干扰素信号、免疫细胞黏附和迁移以及NF-kappa-beta等通路则下调。这些结果提示，具有独特分子特征的特定密度亚型可能比其他亚型更能促进肿瘤发生。为更好地理解这一关联并确定致密乳腺与TNBC样本的常驻细胞之间是否存在相似性，我们正在开展空间生物学分析以探究其微环境。对这些亚型的准确分类有望影响乳腺癌预防策略和早期诊断。目前正在开展更大队列的进一步研究，以更好地理解致密群组中的分子改变如何促进肿瘤发生。
查看英文原文 English abstract
Breast density is a significant independent risk factor for breast cancer; women with dense breasts have a 4-6-fold increased risk of the disease compared to women with non-dense breasts. It has been suggested that 30% of all breast cancer cases occur in women with > 50% dense areas. Breast density reflects variations in breast tissue composition. It is characterized by high proportions of stroma, containing collagen and other ECM proteins, fibroblasts, endothelial cells, and immune cells, suggesting a pro-tumor inflammatory microenvironment. To investigate molecular differences between dense and nondense breast tissue and their association with triple-negative breast cancer (TNBC), we used the PanCancer IO 360 panel to explore RNA expression and signaling pathway regulation across the samples. We observed differences in RNA expression among subjects, thereby identifying distinct molecular groups in dense breasts. The subjects were clustered into 3 subtypes with distinct molecular signatures and biological pathways. We identified a group (G1) with increased expression of genes involved in inflammatory processes, but still maintains a closer association with the phenotype of non-dense breasts. We also identified two other groups (G2 and G3) that are more distinct regarding the non-dense group and different from each other. These groups are related to reorganization and cellular architecture in the microenvironment (G2) and to proliferative regulation, cancer pathways, and increased gene expression in tumor development (G3). These groups do not seem to correlate with age or menopause stage in this first screen; instead, they resemble more subtypes of density or stages of density development. Additionally, analyzing RNA expression in TNBC samples, we identify an association with dense G3 samples that express more RNAs related to DNA repair, with upregulation of pathways in DNA damage, epigenetic regulation, apoptosis, and metabolic stress. At the same time, the pathways such as interferon signaling, immune cell adhesion and migration, and NF-kappa-beta are downregulated. These results suggest that specific density subtypes with distinct molecular signatures may promote tumor development more than others. To better understand this association and determine whether there are similarities in the resident cells of dense breast and TNBC samples, we are conducting spatial biology analyses to explore their microenvironments. The accurate classification of these subtypes has the potential to impact breast cancer prevention strategies and early diagnosis. Further investigations with a larger cohort are underway to understand better how molecular alterations in dense groups contribute to tumor development.
利益披露 Disclosure
N. Dworak, None..
P. Pramoonjago, None..
A. de Oliveira, None.