Role of the Nuclear Receptor Coactivator AIB1/SRC-3 in Angiogenesis and Wound Healing

Abstract

The nuclear receptor coactivator amplified in breast cancer 1 (AIB1/SRC-3) has a well-defined role in steroid and growth factor signaling in cancer and normal epithelial cells. Less is known about its function in stromal cells, although AIB1/SRC-3 is up-regulated in tumor stroma and may, thus, contribute to tumor angiogenesis. Herein, we show that AIB1/SRC-3 depletion from cultured endothelial cells reduces their proliferation and motility in response to growth factors and prevents the formation of intact monolayers with tight junctions and of endothelial tubes. In AIB1/SRC-3(+/-) and (-/-) mice, the angiogenic responses to subcutaneous Matrigel implants was reduced by two-thirds, and exogenously added fibroblast growth factor (FGF) 2 did not overcome this deficiency. Furthermore, AIB1/SRC-3(+/-) and (-/-) mice showed similarly delayed healing of full-thickness excisional skin wounds, indicating that both alleles were required for proper tissue repair. Analysis of this defective wound healing showed reduced recruitment of inflammatory cells and macrophages, cytokine induction, and metalloprotease activity. Skin grafts from animals with different AIB1 genotypes and subsequent wounding of the grafts revealed that the defective healing was attributable to local factors and not to defective bone marrow responses. Indeed, wounds in AIB1(+/-) mice showed reduced expression of FGF10, FGFBP3, FGFR1, FGFR2b, and FGFR3, major local drivers of angiogenesis. We conclude that AIB1/SRC-3 modulates stromal cell responses via cross-talk with the FGF signaling pathway.

NCOA3-mediated upregulation of mucin expression via transcriptional and post-translational changes during the development of pancreatic cancer

“…NCOA3 is a p160SRC family homolog that functions as a nuclear receptor co-activator by interacting with steroid receptors and possesses an intrinsic histone acetyltransferase activity. 16, 17 Studies have demonstrated several roles for NCOA3, it is involved in the maintenance of pluripotency, 30 angiogenesis, wound healing, 31 metabolic defects 32 and immunomodulation. 33 NCOA3 locus is amplified in breast (9.5%) 34 and colorectal cancers (27.5% gain in copy number), 35 that highlights its oncogenic potential.…”

Steroid receptor coactivator-3 as a potential molecular target for cancer therapy

“…However, less is known about the SRC-3 function in stroma. A recent study elucidates the role of SRC-3 in angiogenesis and wound healing 58 . SRC-3 was shown to promote proliferation and motility of endothelial cells, such that neoangiogenesis was dependent on the presence of SRC-3 58 .…”

“…A recent study elucidates the role of SRC-3 in angiogenesis and wound healing 58 . SRC-3 was shown to promote proliferation and motility of endothelial cells, such that neoangiogenesis was dependent on the presence of SRC-3 58 . The study also demonstrated that both alleles of SRC-3 were required for proper wound healing in vivo and that SRC-3 may cross-talk with FGF (fibroblast growth factor) signaling to regulate wound healing process 58 .…”

ERK3 Promotes Endothelial Cell Functions by Upregulating SRC‐3/SP1‐Mediated VEGFR2 Expression

“…SRC‐3 integrates multiple signaling pathways to regulate cell proliferation, migration and invasion (Zhou et al, ; Long et al, ), and has been characterized as a bona fide oncogene with amplification and/or overexpression in multiple human cancers (Anzick et al, ; Torres‐Arzayus et al, ; Tien and Xu, ). In addition to its functions in epithelial cells, SRC‐3 was also shown to be important for the functions of endothelial cells including in vivo angiogenesis (Fereshteh et al, ; Ying et al, ; Al‐Otaiby et al, ). The molecular mechanisms underlying SRC‐3's function in endothelial cells, however, are largely unknown.…”

“…The role of ERK3 signaling in angiogenesis, however, remains to be explored. Importantly, both of the two known EKR3 substrates, SRC‐3 and MK5, are known to positively regulate angiogenesis (Al‐Otaiby et al, ; Yoshizuka et al, ), suggesting that ERK3 may play a similar role in this process. The functional activity of a protein kinase is regulated by both its gene expression level and its protein enzymatic activation.…”