Breast cancer remains the leading cause of cancer-related death in women worldwide. This disease is characterized by its molecular and phenotypic heterogeneity, which hinders the development of effective therapies. While two-dimensional (2D) monolayer cell cultures are widely used, they are insufficient to reproduce the characteristics of the tumor microenvironment, thus limiting our understanding of cancer biology. In this context, three-dimensional (3D) models have emerged as representative tools that more accurately reproduce tissue architecture, cell signaling, and nutrients and oxygen gradients. These cellular models offer greater similarity to primary tissues, improving the study of relevant biological processes. Although 3D cultures provide numerous advantages in cancer research, there is no unified model that standardizes the matrix type and parameters such as gelation time or porosity, hindering the reproducibility and interpretability of the data. This review integrates evidence from various studies to evaluate the effect of epigenetic variations generated by 3D culture methods, which are regulated by mechanotransduction and, consequently, by signaling pathways such as integrin/FAK-ILK/Rho-YAP derived from interactions of cells with extracellular matrix-enriched scaffolds. This affects processes such as DNA methylation, histone coding, and the regulation of non-coding RNAs such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in different molecular subtypes of breast cancer. Overall, the evidence highlights that 3D culture methods are not equivalent but rather generate distinct epigenetic signatures at the non-coding RNA level that influence the proliferation, differentiation, therapeutic resistance, and metastatic potential of tumor cells. Furthermore, the evidence suggests that histone coding patterns, primarily through the reduction of acetylation marks, are conserved regardless of the type of 3D culture. In summary, the study highlights that the microarchitectural and compositional characteristics of 3D scaffolds are key determinants of epigenetic plasticity.
乳腺癌仍是全球女性癌症相关死亡的首要原因。该疾病具有分子和表型异质性特征，这阻碍了有效疗法的开发。虽然二维单层细胞培养被广泛使用，但其不足以重现肿瘤微环境的特征，从而限制了对癌症生物学的理解。在此背景下，三维模型已成为更具代表性的工具，能更准确地再现组织结构、细胞信号传导以及营养物质和氧梯度。这些细胞模型与原始组织具有更高的相似性，有助于改进相关生物学过程的研究。尽管三维培养在癌症研究中具有诸多优势，但目前尚无统一模型来标准化基质类型及凝胶时间或孔隙率等参数，这阻碍了数据的可重复性和可解释性。本综述整合了多项研究证据，旨在评估三维培养方法产生的表观遗传变异效应——这些变异受机械转导调控，并由此受到细胞与富含细胞外基质的支架相互作用所衍生的整合素/FAK-ILK/Rho-YAP等信号通路的影响。这影响了乳腺癌不同分子亚型中DNA甲基化、组蛋白编码以及microRNA、长链非编码RNA和环状RNA等非编码RNA的调控过程。总体而言，证据表明三维培养方法并非等效，而是在非编码RNA水平产生不同的表观遗传特征，进而影响肿瘤细胞的增殖、分化、治疗抵抗和转移潜能。此外，研究显示无论采用何种三维培养类型，组蛋白编码模式（主要通过乙酰化标记的减少）均保持保守。综上所述，本研究强调三维支架的微观结构和组成特征是表观遗传可塑性的关键决定因素。
Epigenetic and Transcriptional Reprogramming in 3D Culture Models in Breast Cancer
肿瘤(癌症)患者之家