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Oncogene (2011) 30, 33813390
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ORIGINAL ARTICLE
Mutation of thyroid hormone receptor-b in mice predisposes to the development of mammary tumors
CJ Guigon1, DW Kim1, MC Willingham2 and S-y Cheng1
1Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA and 2Department of Pathology, Wake Forest University, Winston-Salem, NC, USA
Correlative data suggest that thyroid hormone receptor-b (TRb) mutations could increase the risk of mammary tumor development, but unequivocal evidence is still lacking. To explore the role of TRb mutants in vivo in breast tumor development and progression, we took advantage of a knock-in mouse model harboring a mutation in the Thrb gene encoding TRb (ThrbPV mouse).
Although in adult nulliparous females, a single ThrbPV allele did not contribute to mammary gland abnormalities, the presence of two ThrbPV alleles led to mammary hyperplasia in B36% ThrbPV/PV mice. The ThrbPV
mutation further markedly augmented the risk of mammary hyperplasia in a mouse model with high susceptibility to mammary tumors (Pten/ mouse), as demonstrated by the occurrence of mammary hyperplasia in B60% of ThrbPV/Pten/ and B77% of ThrbPV/PV
Pten/ mice versus B33% of Thrb/Pten/ mice. The ThrbPV mutation increased the activity of signal transducer and activator of transcription (STAT5) to increase cell proliferation and the expression of the STAT5 target gene encoding b-casein in the mammary gland. We next sought to understand the molecular mechanism underlying STAT5 overactivation by TRbPV. Cell-based studies with a breast cancer cell line (T47D cells) showed that thyroid hormone (T3) repressed STAT5 signaling in TRb-expressing cells through decreasing STAT5-mediated transcription activity and target gene expression, whereas sustained STAT5 signaling was observed in TRbPV-expressing cells. Collectively, these ndings show for the rst time that a TRb mutation promotes the development of mammary hyperplasia via aberrant activation of STAT5, thereby conferring a fertile genetic ground for tumorigenesis.
Oncogene (2011) 30, 33813390; doi:http://dx.doi.org/10.1038/onc.2011.50
Web End =10.1038/onc.2011.50 ; published online 14 March 2011
Keywords: thyroid hormone receptor; breast cancer; mammary tumors; Pten; mouse models
Introduction
Thyroid hormone receptors (TRs) belong to the superfamily of nuclear receptors that are ligand-dependent transcription factors. Two TR genes, THRA and THRB, located on chromosomes 17 and 3, respectively, encode four thyroid hormone (T3)-binding receptors:...