Mutation of thyroid hormone receptor β promotes development of breast tumors

CELINE J GUIGON; LAURA FOZZATTI; MARK C WILLINGHAM; SHEUE-YANN CHENG

Washington DC

Congreso; The 91st ANNUAL MEETING, ENDO 2009; 2009

The Endocrine Society

Breast cancer is the leading cause of cancer-related death in women worldwide. Mutations of thyroid hormone receptors (TR) are closely associated with breast cancers, but their possible involvement in the disease is still unclear. To explore their role in vivo in breast cancer development and progression, we took advantage of a knock-in mouse model harboring a mutation in the TRβ gene (TRβPV mouse). The TRβPV mutation consists of a C-terminal 14 amino acid frame shift and leads to the loss of T3 binding capacity and potent dominant negative activity. Analysis by real-time RT-PCR showed that TRβ and TRβPV were expressed in the mammary glands of wild-type and TRβPV mice, respectively (~45% of that found in the liver). To study the possible effect of TRβPV on mammary gland tumorigenesis as well as in a mouse model at high risk for mammary tumor development (Pten+/- mouse), TRβPV/+, TRβPV/PV, TRβPV/+Pten+/- and TRβPV/PVPten+/- mice were generated. Morphological analysis by mammary gland whole mounts in virgin mice aged 3-12 months showed that 33% of TRβPV/PV, but none of the TRβPV/+ or wild-type mice, displayed preneoplastic lesions characterized by lobulo-alveolar branching and ductal dilatation similar to those in lactating mammary glands. The TRβPV mutation further increased the occurrence of preneoplastic lesions in Pten+/- mice: they were found in 50% of TRβPV/+Pten+/- and 62.5% of TRβPV/PVPten+/- mice as compared with 27.2% of Pten+/- mice. Consistently, real-time RT-PCR analyses showed a 3- to 5-fold increase in the levels of the milk protein transcripts β-casein and α-lactalbumin in TRβPV/PV, TRβPV/+Pten+/-, and TRβPV/PVPten+/- mammary glands as compared with the other groups. The appearance of preneoplastic lesions can proceed to mammary gland tumorigenesis. Indeed, we found fibroadenomas and carcinomas in both TRβPV/+Pten+/- and Pten+/- mice. Notably, there was a significant increase in the occurrence of fibroadenomas in TRβPV/+Pten+/- mice as compared with Pten+/- mice (40% versus 25%, n=16-40). Taken together, our results provide evidence for the first time that a TRβ mutant, TRβPV, promotes the development of preneoplastic lesions in the mammary gland, thereby conferring a fertile genetic ground for tumor development and progression.