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. 2024 Apr 10;15(4):256. doi: 10.1038/s41419-024-06637-2

Fig. 7. Spry downregulation and activated fibroblast expansion in breast cancer.

Fig. 7

A Spry1, Spry2, and Spry4 mRNA expression in human breast cancer subtypes using the TCGA database. (B, C) Spry1, Spry2, and Spry4 mRNA expression in stromal fibroblasts of human breast cancer samples (B) or a mouse model of breast cancer using the 4T1 cells (C). D, E Size distribution of the MSF1-4 subgroups in the control and 4T1 cancer fibroblasts of the mouse (D) or human breast cancer (E). Numbers in parenthesis indicate sample numbers. F, F’ Schematic diagram of the process of differentiation and expansion of activated fibroblasts in mammary gland development and breast cancer. F Activated fibroblasts of the MSF-2 subgroup are derived from progenitors in the MSF-1, MSF-3, and MSF-4 subgroups, presumably due to interactions between the stromal microenvironment and the epithelium actively undergoing invasion and branch-formation. Epithelial-derived ligands of the EGF and IGF families further promotes MSF-2 subgroup expansion via RTK signaling, which is negatively regulated by the Spry genes. Activated fibroblasts in the MSF-2 subgroup are responsible for the production of branching factors, e.g., FGF10, to promote epithelial development in the mammary gland. F’ Upon downregulation of Spry functions, e.g., when the Spry genes are knocked out in the mutant mammary glands or their functions are otherwise silenced in breast cancer, multiple pathways of RTK signaling, especially EGFR and IGFR signaling are increased. This leads to an over-expansion of the activated fibroblast population and, consequently, over-production of branching factors such as FGF10. As a result, epithelial development is accelerated, as manifested in precocious branching morphogenesis in Spry-null glands or breast cancer development in mice and humans: Diff. Differentiation, Expa. Expansion, TEB terminal end bud.