Abstract
Simple SummaryKnowledge of the transcriptional regulation of breast cancer tumorigenesis is largely based on studies performed in two-dimensional (2D) monolayer culture models, which lack tissue architecture and therefore fail to represent tumor heterogeneity. However, three-dimensional (3D) cell culture models are better at mimicking in vivo tumor microenvironment, which is critical in regulating cellular behavior. Hence, 3D cell culture models hold great promise for translational breast cancer research.Intratumor heterogeneity of breast cancer is driven by extrinsic factors from the tumor microenvironment (TME) as well as tumor cell–intrinsic parameters including genetic, epigenetic, and transcriptomic traits. The extracellular matrix (ECM), a major structural component of the TME, impacts every stage of tumorigenesis by providing necessary biochemical and biomechanical cues that are major regulators of cell shape/architecture, stiffness, cell proliferation, survival, invasion, and migration. Moreover, ECM and tissue architecture have a profound impact on chromatin structure, thereby altering gene expression. Considering the significant contribution of ECM to cellular behavior, a large body of work underlined that traditional two-dimensional (2D) cultures depriving cell–cell and cell–ECM interactions as well as spatial cellular distribution and organization of solid tumors fail to recapitulate in vivo properties of tumor cells residing in the complex TME. Thus, three-dimensional (3D) culture models are increasingly employed in cancer research, as these culture systems better mimic the physiological microenvironment and shape the cellular responses according to the microenvironmental cues that will regulate critical cell functions such as cell shape/architecture, survival, proliferation, differentiation, and drug response as well as gene expression. Therefore, 3D cell culture models that better resemble the patient transcriptome are critical in defining physiologically relevant transcriptional changes. This review will present the transcriptional factor (TF) repertoire of breast cancer in 3D culture models in the context of mammary tissue architecture, epithelial-to-mesenchymal transition and metastasis, cell death mechanisms, cancer therapy resistance and differential drug response, and stemness and will discuss the impact of culture dimensionality on breast cancer research.
Highlights
Breast cancer (BC) is characterized by phenotypic and molecular heterogeneity that differs within each patient as well as distinct genomic and biological features that differ within a tumor [1]
Despite the advantages of well-established and proven 2D culture models, they lack 3D spatial cellular distribution and organization of solid tumors, which limits these models to reflect in vivo properties of cancer
A wide range of 3D platforms has been manufactured for BC cell culture including scaffold-free spheroids, scaffold-based systems, microfluidic devices, and 3D bioprinting [206]
Summary
Breast cancer (BC) is characterized by phenotypic and molecular heterogeneity that differs within each patient (intertumoral heterogeneity) as well as distinct genomic and biological features that differ within a tumor (intratumor heterogeneity) [1]. Knockdown of endogenous Runx or stable expression of functionally deficient mutant versions of Runx restored organized acini structures in metastatic MDA-MB-231 in 3D culture and failed to promote tumor growth in vivo [91] Another TF regulating mammary tissue architecture is SOX7, a tumor suppressor gene located on human chromosome 8, which is frequently lost in breast tumors [92]. MZF1 (Myeloid zinc finger 1), which is known as the oncogenic TF in various solid cancers, has a critical role in trans-differentiation of mesenchymal stem cells (MSC) into carcinoma-associated fibroblast (CAF)-like cells to promote tumor growth and metastases in BC [130,131] Another EMT-related TF studied in 3D culture models is ZEB1, a zinc-finger E-box-binding TF that regulates expression of E- and N-cadherins. They demonstrated that TGF-β-induced EMT is dependent on CCR7 for targeted dissemination towards the lymphatic system in a mouse model and in a 3D co-culture system [140]
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