title: 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.
authors.affiliation: Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA.
authors.forename: Maram
authors.initials: M
authors.lastname: Al-Otaiby
authors.forename: Elena
authors.initials: E
authors.lastname: Tassi
authors.forename: Marcel O
authors.initials: MO
authors.lastname: Schmidt
authors.forename: Chris D
authors.initials: CD
authors.lastname: Chien
authors.forename: Tabari
authors.initials: T
authors.lastname: Baker
authors.forename: Armando Ganoza
authors.initials: AG
authors.lastname: Salas
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Mary
authors.initials: M
authors.lastname: Furlong
authors.forename: Richard
authors.initials: R
authors.lastname: Schlegel
authors.forename: Anna T
authors.initials: AT
authors.lastname: Riegel
authors.forename: Anton
authors.initials: A
authors.lastname: Wellstein
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003094:Collagen; D004338:Drug Combinations; D005346:Fibroblast Growth Factors / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D007797:Laminin; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D056921:Nuclear Receptor Coactivator 3 / Q000172:deficiency / Q000502:physiology*; D011509:Proteoglycans; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000098:blood supply / Q000293:injuries* / Q000378:metabolism; D012879:Skin Physiological Phenomena; D016038:Skin Transplantation / Q000379:methods; D017154:Stromal Cells / Q000502:physiology; D014945:Wound Healing / Q000502:physiology*
chemical_list: D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D005346:Fibroblast Growth Factors; D003094:Collagen; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3