The role of nuclear receptor coactivator AIB1/SRC3 in normal and breast cancer stromal functions

The nuclear receptor coactivator amplified in breast cancer 1 (AIB1/SRC3) 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, though AIB1/SRC3 is upregulated in tumor stroma and may thus contribute to tumor angiogenesis. In addition, our lab has demonstrated previously a potential impact of AIB1/SRC3 on tumor stroma as reduced angiogenesis was observed in mammary tumors in AIB1/SRC3 knockout mice. In this study, we report for the first time the effect of AIB1/SRC3 on the function of two types of stromal cells and on keratinocytes in vitro. Endothelial cell functions including formation of tube like structures, monolayer formation, migration, proliferation and apoptosis were all inhibited by reduction in AIB1. We also observed reduction on FGF2-induced signaling of endothelial cells in vitro when AIB1/SRC3 levels were reduced. Moreover, AIB1/SRC3 did not impact fibroblast proliferation, but did impact its migration. We also observed that AIB1/SRC3 had a significant effect on keratinocyte proliferation through the up regulation of a number of cell cycle molecules. In AIB1/SRC3+/- and AIB1/SRC3 -/- mice, the angiogenic responses to subcutaneous Matrigel implants were reduced by two thirds and exogenously added FGF2 did not overcome this deficiency. Furthermore, AIB1/SRC3+/- and AIB1/SRC3 -/- mice showed a 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 genotype and subsequent wounding of the grafts revealed that the defective healing is attributable to local factors and not to defective bone marrow responses. Indeed, wounds in AIB1/SRC3 +/- mice showed reduced expression of FGF10, FGFBP3, FGFR1, FGFR2b and FGFR3, major local drivers of angiogenesis. Further, we examined the influence of AIB1/SRC3 in the epithelial and stromal cross talk in breast cancer. We reported that AIB1/SRC3 has a critical role in the stromal compartment during mammary tumor development. The loss of one allele of AIB1/SRC3 in the stroma significantly delayed tumorigenesis.