title: Role of Prolactin Receptors in Lymphangioleiomyomatosis.
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.
authors.affiliation: Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.|Sultan Qaboos University, College of Medicine and Health Sciences, Muscat, Oman.
authors.forename: Amira
authors.initials: A
authors.lastname: Alkharusi
authors.affiliation: Department of Health Sciences, Laboratories of Pharmacology, Università degli Studi di Milano, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Lesma
authors.affiliation: Department of Health Sciences, Laboratories of Pharmacology, Università degli Studi di Milano, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ancona
authors.affiliation: Department of Health Sciences, Laboratories of Pharmacology, Università degli Studi di Milano, Milano, Italy.
authors.forename: Eloisa
authors.initials: E
authors.lastname: Chiaramonte
authors.affiliation: Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nyström
authors.affiliation: Department of Health Sciences, Laboratories of Pharmacology, Università degli Studi di Milano, Milano, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Gorio
authors.affiliation: Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Norstedt
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D018192:Lymphangioleiomyomatosis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D011981:Receptors, Prolactin; D050796:STAT3 Transcription Factor; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D048049:Extracellular Signal-Regulated MAP Kinases