title: Characterization of the mTOR pathway in human normal adrenal and adrenocortical tumors.
abstract: The mTOR pathway has recently been suggested as a new potential target for therapy in adrenocortical carcinomas (ACCs). The aim of the current study is to describe the expression of the mTOR pathway in normal adrenals (NAs) and pathological adrenals and to explore whether there are correlation between the expression of these proteins and the in vitro response to sirolimus. For this purpose, the MTOR, S6K1 (RPS6KB1), and 4EBP1 (EIF4EBP1) mRNA expression were evaluated in ten NAs, ten adrenal hyperplasias (AHs), 17 adrenocortical adenomas (ACAs), and 17 ACCs by qPCR, whereas total(t)/phospho(p)-MTOR, t/p-S6K, and t/p-4EBP1 protein expression were assessed in three NAs, three AHs, six ACAs, and 20 ACCs by immunohistochemistry. The effects of sirolimus on cell survival and/or cortisol secretion in 12 human primary cultures of adrenocortical tumors (ATs) were also evaluated. In NAs and AHs, layer-specific expression of evaluated proteins was observed. S6K1 mRNA levels were lower in ACCs compared with NAs, AHs, and ACAs (P<0.01). A subset of ATs presented a moderate to high staining of the evaluated proteins. Median t-S6K1 protein expression in ACCs was lower than that in ACAs (P<0.01). Moderate to high staining of p-S6K1 and/or p-4EBP1 was observed in most ATs. A subset of ACCs not having moderate to high staining had a higher Weiss score than others (P<0.029). In primary AT cultures, sirolimus significantly reduced cell survival or cortisol secretion only in sporadic cases. In conclusion, these data suggest the presence of an activated mTOR pathway in a subset of ATs and a possible response to sirolimus only in certain ACC cases.
authors.affiliation: Department of Internal MedicineDivision of Endocrinology, Erasmus Medical Center, Rotterdam, The NetherlandsDipartimento di Medicina Clinica e ChirurgiaSezione di Endocrinologia, Università Federico II, Naples, ItalyDepartment of PathologyErasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: De Martino
authors.affiliation: Department of Internal MedicineDivision of Endocrinology, Erasmus Medical Center, Rotterdam, The NetherlandsDipartimento di Medicina Clinica e ChirurgiaSezione di Endocrinologia, Università Federico II, Naples, ItalyDepartment of PathologyErasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Feelders
authors.affiliation: Department of Internal MedicineDivision of Endocrinology, Erasmus Medical Center, Rotterdam, The NetherlandsDipartimento di Medicina Clinica e ChirurgiaSezione di Endocrinologia, Università Federico II, Naples, ItalyDepartment of PathologyErasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands.
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.affiliation: Department of Internal MedicineDivision of Endocrinology, Erasmus Medical Center, Rotterdam, The NetherlandsDipartimento di Medicina Clinica e ChirurgiaSezione di Endocrinologia, Università Federico II, Naples, ItalyDepartment of PathologyErasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Koetsveld
authors.affiliation: Department of Internal MedicineDivision of Endocrinology, Erasmus Medical Center, Rotterdam, The NetherlandsDipartimento di Medicina Clinica e ChirurgiaSezione di Endocrinologia, Università Federico II, Naples, ItalyDepartment of PathologyErasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands.
authors.forename: Fadime
authors.initials: F
authors.lastname: Dogan
authors.affiliation: Department of Internal MedicineDivision of Endocrinology, Erasmus Medical Center, Rotterdam, The NetherlandsDipartimento di Medicina Clinica e ChirurgiaSezione di Endocrinologia, Università Federico II, Naples, ItalyDepartment of PathologyErasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands.
authors.forename: Joseph A M J L
authors.initials: JA
authors.lastname: Janssen
authors.affiliation: Department of Internal MedicineDivision of Endocrinology, Erasmus Medical Center, Rotterdam, The NetherlandsDipartimento di Medicina Clinica e ChirurgiaSezione di Endocrinologia, Università Federico II, Naples, ItalyDepartment of PathologyErasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands.
authors.forename: A Marlijn
authors.initials: AM
authors.lastname: Waaijers
authors.affiliation: Department of Internal MedicineDivision of Endocrinology, Erasmus Medical Center, Rotterdam, The NetherlandsDipartimento di Medicina Clinica e ChirurgiaSezione di Endocrinologia, Università Federico II, Naples, ItalyDepartment of PathologyErasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pivonello
authors.affiliation: Department of Internal MedicineDivision of Endocrinology, Erasmus Medical Center, Rotterdam, The NetherlandsDipartimento di Medicina Clinica e ChirurgiaSezione di Endocrinologia, Università Federico II, Naples, ItalyDepartment of PathologyErasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands.
authors.forename: Steven W J
authors.initials: SW
authors.lastname: Lamberts
authors.affiliation: Department of Internal MedicineDivision of Endocrinology, Erasmus Medical Center, Rotterdam, The NetherlandsDipartimento di Medicina Clinica e ChirurgiaSezione di Endocrinologia, Università Federico II, Naples, ItalyDepartment of PathologyErasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colao
authors.affiliation: Department of Internal MedicineDivision of Endocrinology, Erasmus Medical Center, Rotterdam, The NetherlandsDipartimento di Medicina Clinica e ChirurgiaSezione di Endocrinologia, Università Federico II, Naples, ItalyDepartment of PathologyErasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.affiliation: Department of Internal MedicineDivision of Endocrinology, Erasmus Medical Center, Rotterdam, The NetherlandsDipartimento di Medicina Clinica e ChirurgiaSezione di Endocrinologia, Università Federico II, Naples, ItalyDepartment of PathologyErasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands.
authors.forename: Rosario
authors.initials: R
authors.lastname: Pivonello
authors.affiliation: Department of Internal MedicineDivision of Endocrinology, Erasmus Medical Center, Rotterdam, The NetherlandsDipartimento di Medicina Clinica e ChirurgiaSezione di Endocrinologia, Università Federico II, Naples, ItalyDepartment of PathologyErasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands l.hofland@erasmusmc.nl.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000302:Adrenal Cortex / Q000378:metabolism / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism; D018246:Adrenocortical Adenoma / Q000235:genetics* / Q000378:metabolism; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D020123:Sirolimus
keywords: adenoma; adrenal cortex; adrenocortical cancer; carcinoma; immunohistochemistry; mTOR; primary cultures