Related Experiment Video
Updated: Aug 26, 2025
X-Ray Visualization of Intraductal Ethanol-Based Ablative Treatment for Prevention of Breast Cancer in Rat Models
Published on: December 9, 2022
TLR4 inhibition suppresses growth in oestrogen-induced prolactinoma models
Yu Zhang1,2,3, Li Ma1, Shuguang Dong4
1Department of Pharmacy, Tongren hospital affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, China.
Abstract:
Prolactinomas have harmful effects on human health. Bromocriptine is the only commercially available drug in China, but about 25% of prolactinoma patients do not respond to it in clinic, its pathogenesis remains unknown. Thus, its pathogenesis needs to be determined to develop new therapeutic methods for prolactinomas. The expression of ERβ, TLR4, and prolactin (PRL) in the pituitary gland of C57BL/6 mice and human prolactinoma specimen was examined by immunofluorescence or immunohistochemistry. The role of TLR4 in prolactinoma was determined using estradiol-induced models of C57BL/6 wild-type and TLR4-/- mice. MMQ cells were treated with estradiol, fulvestrant, and lipopolysaccharide (LPS) or transfected with TLR4 siRNA to study the expression of ERβ, TLR4, and PRL in these cells. Furthermore, the interaction between ERβ and TLR4 was investigated by immunoprecipitation analysis. The expression of PRL and TLR4 was co-located and increased in the pituitary gland of mice and human prolactinoma specimen compared to that in the control specimen. Meanwhile, TLR4 knockout or treatment with the TLR4 inhibitor TAK242 not only significantly inhibited tumor overgrowth but also decreased the expression of PRL in estradiol-treated mice through p38 MAPK pathway regulation. However, MMQ treated with estradiol and LPS enhanced PRL expression than treated with estradiol or LPS alone. Finally, ERβ or TLR4 inhibition prevented the estradiol-induced PRL increase by regulating the TLR4/p38 MAPK pathway in vitro. Estradiol promoted prolactinoma development by activating the TLR4/p38 MAPK pathway through ERβ, and TLR4 is a potential therapeutic target for prolactinoma treatment.
Insights
Prolactinomas develop when estradiol activates the TLR4/p38 MAPK pathway via ERβ. Targeting TLR4 offers a new therapeutic strategy for prolactinoma treatment.
Area of Science:
- Endocrinology
- Oncology
- Immunology
Background:
- Prolactinomas are detrimental to human health, with current treatments like bromocriptine being ineffective for approximately 25% of patients.
- The underlying pathogenesis of prolactinoma remains largely unknown, necessitating further research for novel therapeutic development.
- Estrogen receptor beta (ERβ) and Toll-like receptor 4 (TLR4) are implicated in various cellular processes and warrant investigation in prolactinoma.
Purpose of the Study:
- To elucidate the pathogenesis of prolactinoma by examining the roles of ERβ, TLR4, and prolactin (PRL).
- To investigate the therapeutic potential of targeting TLR4 in prolactinoma.
- To understand the interaction between ERβ and TLR4 in the context of prolactinoma development.
Main Methods:
- Immunofluorescence and immunohistochemistry were used to assess ERβ, TLR4, and PRL expression in mouse pituitary glands and human prolactinoma specimens.
- Estradiol-induced prolactinoma models in wild-type and TLR4 knockout mice were employed.
- In vitro studies involved treating MMQ cells with estradiol, fulvestrant, lipopolysaccharide (LPS), or TLR4 siRNA, followed by immunoprecipitation analysis to study ERβ-TLR4 interactions.
Main Results:
- Elevated co-localization and expression of PRL and TLR4 were observed in both mouse and human prolactinoma tissues compared to controls.
- TLR4 knockout or inhibition significantly reduced tumor growth and PRL expression in estradiol-treated mice, mediated by the p38 MAPK pathway.
- Estradiol and LPS synergistically increased PRL expression in MMQ cells, while ERβ or TLR4 inhibition counteracted estradiol-induced PRL elevation via the TLR4/p38 MAPK pathway.
Conclusions:
- Estradiol promotes prolactinoma development by activating the TLR4/p38 MAPK pathway through ERβ.
- TLR4 plays a crucial role in prolactinoma pathogenesis and represents a potential therapeutic target.
- Targeting the TLR4/p38 MAPK pathway offers a promising strategy for developing new prolactinoma treatments.
Related Concept Videos
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:22PI3K/mTOR/AKT Signaling Pathway