The steroid receptor coactivator-3 is a tumor promoter in a mouse model of thyroid cancer.

The molecular genetic events underlying thyroid carcinogenesis are not well understood. Mice harboring a dominant-negative mutant thyroid hormone receptor-beta (TRbeta(PV/PV) mice) spontaneously develop follicular thyroid carcinoma similar to human cancer. The present study aimed to elucidate the role of the steroid receptor coactivator-3 (SRC-3) in thyroid carcinogenesis in vivo by using the offspring from the cross of TRbeta(PV/PV) and SRC-3(-/-) mice. TRbeta(PV/PV) mice deficient in SRC-3 (TRbeta(PV/PV)SRC-3(-/-) mice) had significantly increased survival, decreased thyroid tumor growth, delayed tumor progression and lower incidence of distant metastasis as compared with TRbeta(PV/PV) mice with SRC-3 (TRbeta(PV/PV)SRC-3(+/+) mice). Further, in vivo and in vitro analyses of multiple signaling pathways indicated that SRC-3 deficiency could lead to (1) inhibition of cell cycle progression at the G(1)/S transition via controlling the expression of cell cycle regulators, such as E2F1; (2) induction of apoptosis by controlling the expression of the Bcl-2 and caspase-3 genes and (3) suppression of neovascularization and metastasis, at least in part, through modulating the vascular endothelial growth factor gene expression. Taken together, SRC-3 could play important roles through regulating multiple target genes and signaling pathways during thyroid carcinogenesis, understanding of which should direct future therapeutic options for thyroid cancer.