Role of the nuclear receptor coactivator AIB1/SRC-3 in angiogenesis and wound healing

Area of Science:

• Molecular Biology
• Cell Biology
• Cancer Research

Background:

• Amplified in breast cancer 1 (AIB1/SRC-3) is known to regulate steroid and growth factor signaling in epithelial cells.
• AIB1/SRC-3 is upregulated in tumor stroma, suggesting a role in tumor angiogenesis.

Purpose of the Study:

• To investigate the function of AIB1/SRC-3 in stromal cells, particularly its role in angiogenesis and tissue repair.
• To elucidate the mechanisms by which AIB1/SRC-3 influences endothelial cell behavior and fibroblast growth factor (FGF) signaling.

Main Methods:

• Depletion of AIB1/SRC-3 in cultured endothelial cells.
• Analysis of angiogenic responses in AIB1/SRC-3(+/-) and (-/-) mice using Matrigel implants.
• Assessment of skin wound healing in AIB1/SRC-3 heterozygous and knockout mice.
• Examination of inflammatory cell recruitment, cytokine induction, and metalloprotease activity in wound sites.
• Analysis of gene expression related to FGF signaling in AIB1/SRC-3 deficient mice.

Main Results:

• AIB1/SRC-3 depletion reduced endothelial cell proliferation, motility, tight junction formation, and tube formation.
• Angiogenic responses to Matrigel implants were significantly reduced in AIB1/SRC-3(+/-) and (-/-) mice.
• Both alleles of AIB1/SRC-3 were required for proper skin wound healing, characterized by delayed repair.
• Defective wound healing involved reduced inflammatory cell recruitment, cytokine induction, and metalloprotease activity.
• Wounds in AIB1(+/-) mice exhibited reduced expression of key FGF signaling pathway components.

Conclusions:

• AIB1/SRC-3 plays a critical role in modulating stromal cell responses, particularly in angiogenesis and tissue repair.
• AIB1/SRC-3 functions, in part, through cross-talk with the FGF signaling pathway.
• Both AIB1/SRC-3 alleles are necessary for effective wound healing and angiogenesis.