Mutation of thyroid hormone receptor-β in mice predisposes to the development of mammary tumors

Abstract

Correlative data suggest that thyroid hormone receptor-β (TRβ) mutations could increase the risk of mammary tumor development, but unequivocal evidence is still lacking. To explore the role of TRβ 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 TRβ (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 ~36% 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 ~60% of Thrbpv/+Pten+/− and ~77% of ThrbPV/PV Pten+/− mice versus ~33% 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 β-casein in the mammary gland. We next sought to understand the molecular mechanism underlying STAT5 overactivation by TRβPV. Cell-based studies with a breast cancer cell line (T47D cells) showed that thyroid hormone (T3) repressed STAT5 signaling in TRβ-expressing cells through decreasing STAT5-mediated transcription activity and target gene expression, whereas sustained STAT5 signaling was observed in TRβPV-expressing cells. Collectively, these findings show for the first time that a TRβ mutation promotes the development of mammary hyperplasia via aberrant activation of STAT5, thereby conferring a fertile genetic ground for tumorigenesis.

Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer

“…Mammary glands with alveolarization could be due to the increased P 4 levels, as P 4 is known to cause alveolarization and milk production (Conneely et al 2003). A previous study also observed increased mammary gland alveolarization in heterozygous PTENKO females, but P 4 levels were not determined (Guigon et al 2011). We also showed that less PTENARKO females appeared to have alveolarized mammary glands compared to PTENKO, further supporting the reduced P 4 levels in PTENARKO compared to PTENKO females.…”

Differential loss of heterozygosity profile on chromosome 3p in ductal and lobular breast carcinomas

“…THRB can act as a transcriptional activator or silencer depending on the presence or absence of its ligand, thyroid hormone triiodothyronine. In addition, Guigon et al [21] demonstrated that TRβ mutation promotes the development of mammary hyperplasia via aberrant activation of the signal transducer and activator of transcription 5A (STAT5) pathway. Alterations in TR expression also were observed in a subset of patients with breast cancer [22].…”

Thyroid Hormone Receptor-β (TRβ) Mediates Runt-Related Transcription Factor 2 (Runx2) Expression in Thyroid Cancer Cells: A Novel Signaling Pathway in Thyroid Cancer

“…Functional loss or modifications of these transcription factors are increasingly recognized in human cancers. Dysregulation of TRs through point and frameshift mutations as well as epigenetic silencing is established in a variety of solid tumors (31)(32)(33)(34)(35)(36)(37)(38)(39)(40). The propensity for reduced expression of TRs, notably TR␤1, as tumorigenesis progresses is consonant with a suppressor role for TR (41)(42)(43).…”