| First Author | Guigon CJ | Year | 2011 |
| Journal | Oncogene | Volume | 30 |
| Issue | 30 | Pages | 3381-90 |
| PubMed ID | 21399657 | Mgi Jnum | J:174634 |
| Mgi Id | MGI:5140265 | Doi | 10.1038/onc.2011.50 |
| Citation | Guigon CJ, et al. (2011) Mutation of thyroid hormone receptor-beta in mice predisposes to the development of mammary tumors. Oncogene 30(30):3381-90 |
| abstractText | Correlative data suggest that thyroid hormone receptor-beta (TRbeta) mutations could increase the risk of mammary tumor development, but unequivocal evidence is still lacking. To explore the role of TRbeta 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 TRbeta (Thrb(PV) 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 approximately 36% Thrb(PV/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 approximately 60% of Thrb(PV/+)Pten(+/-) and approximately 77% of Thrb(PV/PV)Pten(+/-) mice versus approximately 33% of Thrb(+/+)Pten(+/-) mice. The Thrb(PV) 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 beta-casein in the mammary gland. We next sought to understand the molecular mechanism underlying STAT5 overactivation by TRbetaPV. Cell-based studies with a breast cancer cell line (T47D cells) showed that thyroid hormone (T3) repressed STAT5 signaling in TRbeta-expressing cells through decreasing STAT5-mediated transcription activity and target gene expression, whereas sustained STAT5 signaling was observed in TRbetaPV-expressing cells. Collectively, these findings show for the first time that a TRbeta mutation promotes the development of mammary hyperplasia via aberrant activation of STAT5, thereby conferring a fertile genetic ground for tumorigenesis. |
