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.
Ying
H
H
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
Willingham
M C
MC
Cheng
S-Y
SY
D018263:Adenocarcinoma, Follicular / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009389:Neovascularization, Pathologic / Q000235:genetics; D056921:Nuclear Receptor Coactivator 3; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000235:genetics; D013964:Thyroid Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
D019253:Proto-Oncogene Proteins c-bcl-2; D037042:Thyroid Hormone Receptors beta; D015534:Trans-Activators; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3; D053148:Caspase 3