Role of prolactin receptors in lymphangioleiomyomatosis

Amira Alkharusi, Elena Lesma, Silvia Ancona, Eloisa Chiaramonte, Thomas Nyström, Alfredo Gorio, Gunnar Norstedt

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article number0146653
JournalPLoS One
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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  • Cite this

    Alkharusi, A., Lesma, E., Ancona, S., Chiaramonte, E., Nyström, T., Gorio, A., & Norstedt, G. (2016). Role of prolactin receptors in lymphangioleiomyomatosis. PLoS One, 11(1), [0146653]. https://doi.org/10.1371/journal.pone.0146653