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Molecular network study of pituitary adenomas

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Front. Endocrinol. | doi: 10.3389/fendo.2018.00706

Sex-related differences in lactotroph tumor aggressiveness are associated with a specific gene-expression signature and genome instability

  • 1IUT Lyon1 Génie Biologique, Claude Bernard University Lyon 1, France
  • 2INSERM U1052 Centre de Recherche en Cancerologie de Lyon, France
  • 3ProfileXpert, INSERM US07 Santé Lyon Est Louis Léopold Ollier, France
  • 4CHU Dinant Godinne UCL Namur, Belgium
  • 5Service de Neurochirurgie, Centre Hospitalier Universitaire de Tours, France
  • 6Assistance Publique-Hôpitaux de Paris, Service d’Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l’Hypophyse, Bicêtre Hospital, France
  • 7Service de Neurochirurgie, Hospices Civils de Lyon, Groupement Hospitalier EST, France

Sex-related differences have been reported in various cancers, in particular men with lactotroph tumors have a worse prognosis than women. While the underlying mechanism of this sexual dimorphism remains unclear, it has been suggested that a lower estrogen receptor alpha expression may drive the sex differences observed in aggressive and malignant lactotroph tumors that are resistant to dopamine agonists. Based on this observation, we aimed to explore the molecular importance of the estrogen pathway through a detailed analysis of the transcriptomic profile of lactotroph tumors from 20 men and 10 women. We undertook gene expression analysis of the selected lactotroph tumors following their pathological grading using the five-tiered classification. Chromosomic alterations were further determined in 13 tumors. Functional analysis showed that there were differences between tumors from men and women in gene signatures associated with cell morphology, cell growth, cell proliferation, development, and cell movement. Hundred-forty genes showed an increased or decreased expression with a minimum two-fold change. A large subset of those genes belonged to the estrogen receptor signaling pathway, therefore confirming the potent role of this pathway in lactotroph tumor sex-associated aggressiveness. Genes belonging to the X chromosome, such as CTAG2, FGF13, and VEGF-D, were identified as appealing candidates with a sex-linked dysregulation in lactotroph tumors. Through our comparative genomic hybridization analyses (CGH), chromosomic gain, in particular chromosome 19p, was found only in tumors from men, while deletion of chromosome 11 was sex-independent, as it was found in most (5/6) of the aggressive and malignant tumors. Comparison of transcriptomic and CGH analysis revealed four genes (CRB3, FAM138F, MATK, and STAP2) located on gained regions of chromosome 19 and upregulated in lactotroph tumors from men. MATK and STAP2 are both implicated in cell growth and are reported to be associated with the estrogen signaling pathway. Our work confirms the proposed involvement of the estrogen signaling pathway in favoring the increased aggressiveness of lactotroph tumors in men. More importantly, we highlight a number of ER-related candidate genes and further identify a series of target molecules with sex-specific expression that could contribute to the aggressive behavior of lactotroph tumors in men.

Keywords: Lactotroph tumors, pituitary tumors, Gene Expression, estrogen signaling, sexual dimorphism, chromosome, aggressiveness

Received: 24 Sep 2018; Accepted: 09 Nov 2018.

Edited by:

Hidenori Fukuoka, Kobe University, Japan

Reviewed by:

Giampaolo Trivellin, National Institutes of Health (NIH), United States
Odelia Cooper, Cedars-Sinai Medical Center, United States
Haruhiko Kanasaki, Shimane University, Japan  

Copyright: © 2018 Wierinckx, Delgrange, Bertollino, François, Chanson, Jouanneau, Lachuer, Trouillas and Raverot. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Anne Wierinckx, Claude Bernard University Lyon 1, IUT Lyon1 Génie Biologique, Lyon, France, anne.wierinckx@univ-lyon1.fr