Am J Cancer Res 2013;3(3):302-311
Original Article
Inhibition of estrogen-dependent tumorigenesis by the thyroid hor-mone
receptor β in xenograft models
Jeong Won Park, Li Zhao, Sheue-Yann Cheng
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Received April 11, 2013; Accepted May 20, 2013; Epub June 20, 2013; Published June 30, 2013
Abstract: Association studies suggest that thyroid hormone receptor β (TRβ) could function as a tumor suppressor in breast
cancer development, but unequivocal evidence is still lacking. To understand the role of TRβ in breast tumor development, we
adopted the gain-of-function approach by stably expressing the THRB gene in a human breast cancer cell line, MCF-7 (MCF-7-
TRβ). Parental MCF-7 cells express the estrogen receptor, but not TRs. MCF-7 cells, stably expressing only the selectable
marker, the Neo gene, were also generated as control for comparison (MCF-7-Neo cells). Cell-based studies indicate that the
estrogen (E2)-dependent growth of MCF-7 cells was inhibited by the expression of TRβ in the presence of the thyroid hormone
(T3). In a xenograft mouse model, large tumors rapidly developed after inoculation of MCF-7-Neo cells in athymic mice. In
contrast, markedly smaller tumors (98% smaller) were found when MCF-7-TRβ cells were inoculated in athymic mice, indicating
that TRβ inhibited the E2-dependent tumor growth of MCF-7 cells. Further detailed molecular analysis showed that TRβ acted to
activate apoptosis and decrease proliferation of tumor cells, resulting in inhibition of tumor growth. The TRβ-mediated inhibition
of tumor growth was elucidated via down-regulation of the JAK-STAT-cyclin D pathways. This in vivo evidence shows that TRβ
could act as a tumor suppressor in breast tumorigenesis. The present study provides new insights into the role of TR in breast
cancer. (ajcr0000198).
Keywords: Thyroid hormone receptor beta, tumor suppressor, tumorigenesis, STAT signaling, MCF-7 cells
Address correspondence to: Dr. Sheue-Yann Cheng, Gene regulation section, Laboratory of Molecular Biology, Center for
Cancer Research, National Cancer Institute, 37 Convent Dr, Room 5128, Bethesda, MD 20892-4264, USA. E-mail:
chengs@mail.nih.gov
Original Article
Inhibition of estrogen-dependent tumorigenesis by the thyroid hor-mone
receptor β in xenograft models
Jeong Won Park, Li Zhao, Sheue-Yann Cheng
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Received April 11, 2013; Accepted May 20, 2013; Epub June 20, 2013; Published June 30, 2013
Abstract: Association studies suggest that thyroid hormone receptor β (TRβ) could function as a tumor suppressor in breast
cancer development, but unequivocal evidence is still lacking. To understand the role of TRβ in breast tumor development, we
adopted the gain-of-function approach by stably expressing the THRB gene in a human breast cancer cell line, MCF-7 (MCF-7-
TRβ). Parental MCF-7 cells express the estrogen receptor, but not TRs. MCF-7 cells, stably expressing only the selectable
marker, the Neo gene, were also generated as control for comparison (MCF-7-Neo cells). Cell-based studies indicate that the
estrogen (E2)-dependent growth of MCF-7 cells was inhibited by the expression of TRβ in the presence of the thyroid hormone
(T3). In a xenograft mouse model, large tumors rapidly developed after inoculation of MCF-7-Neo cells in athymic mice. In
contrast, markedly smaller tumors (98% smaller) were found when MCF-7-TRβ cells were inoculated in athymic mice, indicating
that TRβ inhibited the E2-dependent tumor growth of MCF-7 cells. Further detailed molecular analysis showed that TRβ acted to
activate apoptosis and decrease proliferation of tumor cells, resulting in inhibition of tumor growth. The TRβ-mediated inhibition
of tumor growth was elucidated via down-regulation of the JAK-STAT-cyclin D pathways. This in vivo evidence shows that TRβ
could act as a tumor suppressor in breast tumorigenesis. The present study provides new insights into the role of TR in breast
cancer. (ajcr0000198).
Keywords: Thyroid hormone receptor beta, tumor suppressor, tumorigenesis, STAT signaling, MCF-7 cells
Address correspondence to: Dr. Sheue-Yann Cheng, Gene regulation section, Laboratory of Molecular Biology, Center for
Cancer Research, National Cancer Institute, 37 Convent Dr, Room 5128, Bethesda, MD 20892-4264, USA. E-mail:
chengs@mail.nih.gov
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American Journal of Cancer Research
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