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Role of Prolactin Receptors in Lymphangioleiomyomatosis
Amira Alkharusi1,2, Elena Lesma3, Silvia Ancona3
1Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
Abstract:
Pulmonary lymphangioleiomyomatosis (LAM) is a rare lung disease caused by mutations in the tumor suppressor genes encoding Tuberous Sclerosis Complex (TSC) 1 and TSC2. The protein product of the TSC2 gene is a well-known suppressor of the mTOR pathway. Emerging evidence suggests that the pituitary hormone prolactin (Prl) has both endocrine and paracrine modes of action. Here, we have investigated components of the Prl system in models for LAM. In a TSC2 (+/-) mouse sarcoma cell line, down-regulation of TSC2 using siRNA resulted in increased levels of the Prl receptor. In human LAM cells, the Prl receptor is detectable by immunohistochemistry, and the expression of Prl in these cells stimulates STAT3 and Erk phosphorylation, as well as proliferation. A high affinity Prl receptor antagonist consisting of Prl with four amino acid substitutions reduced phosphorylation of STAT3 and Erk. Antagonist treatment further reduced the proliferative and invasive properties of LAM cells. In histological sections from LAM patients, Prl receptor immuno reactivity was observed. We conclude that the Prl receptor is expressed in LAM, and that loss of TSC2 increases Prl receptor levels. It is proposed that Prl exerts growth-stimulatory effects on LAM cells, and that antagonizing the Prl receptor can block such effects.
Insights
Prolactin (Prl) receptor is present in pulmonary lymphangioleiomyomatosis (LAM). Loss of TSC2 increases Prl receptor levels, promoting LAM cell growth. Blocking the Prl receptor inhibits LAM cell proliferation and invasion.
Area of Science:
- Cell Biology
- Endocrinology
- Pulmonology
Background:
- Pulmonary lymphangioleiomyomatosis (LAM) is a rare lung disease linked to mutations in TSC1/TSC2 tumor suppressor genes.
- The TSC2 gene product suppresses the mTOR pathway, and prolactin (Prl) is a pituitary hormone with endocrine and paracrine functions.
Purpose of the Study:
- Investigate the role of the prolactin (Prl) system in LAM.
- Determine if Prl signaling contributes to LAM pathogenesis.
Main Methods:
- Utilized a TSC2 (+/-) mouse sarcoma cell line with siRNA to down-regulate TSC2.
- Examined Prl receptor expression in human LAM cells via immunohistochemistry.
- Assessed the effects of Prl and a Prl receptor antagonist on LAM cell signaling and proliferation.
- Analyzed Prl receptor expression in patient tissue samples.
Main Results:
- Down-regulation of TSC2 increased Prl receptor levels in a mouse sarcoma cell line.
- Human LAM cells express the Prl receptor, and Prl stimulation enhanced STAT3/Erk phosphorylation and proliferation.
- A Prl receptor antagonist reduced STAT3/Erk phosphorylation and inhibited LAM cell proliferation and invasion.
- Prl receptor immunoreactivity was detected in LAM patient tissues.
Conclusions:
- The Prl receptor is expressed in LAM cells, and its levels increase with TSC2 loss.
- Prl promotes LAM cell growth and invasion through its receptor.
- Targeting the Prl receptor with antagonists offers a potential therapeutic strategy for LAM.
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