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Understanding and targeting prolactin signalling in human diseases

from basic science:
  • structure-function
  • tumorigenesis
to the translational research:
  • hormone-dependent tumors
Vincent Goffin
Prolactin and Growth Hormone Pathophysiology: Translational Approaches
Vincent Goffin was trained as a molecular endocrinologist. He graduated at the University of Liège (Belgium) in 1993. After his post-doctoral training at Inserm U344, Paris (Marie-Curie fellowship), he was hired by Inserm as a tenure researcher in 1996. He is currently research director and heads his lab since 2006. Vincent Goffin is internationally recognized as a leader in the field of the prolactin (PRL)/growth hormone (GH) protein family. His main achievements include i) translational research on the role of PRL receptor signaling in various human diseases with particular emphasis in Oncology, and ii) preclinical development of PRL receptor inhibitors based on cutting-edge structure-function studies of receptor activation. He founded the FASEB Science Reaserch Conference “The GH/PRL family in biology & diseases” in 2012 (3rd editionwill be held in 2017) and has been consultant for many companies developing PRL-related projects.

Focus

Use translational approaches to identify, understand and target cellular and molecular mechanisms responsible for the progression and/or resistance to treatment of breast and prostate cancers, with major focus on prolactin and calcium signaling.

Introduction

Due to the increasing lifespan in western countries, cancer incidence will continue to raise in future. When diagnosed at a localized stage, breast and prostate tumors are successfully treated by surgery and/or radiotherapy, which supports routine prevention policies (e.g. PSA screening). The standard of care of more advanced stages of the diseases involves medical treatment (e.g. anti-androgen therapy, chemotherapy). Although some tumors respond well to therapy, de novo or acquired resistance to treatment is frequently observed leading to cancer progression towards lethal metastatic stages. To improve treatment efficacy, combined therapies need to be developed, which requires i) to identify new molecular drivers of tumor progression, and ii) to identify and understand the biology of the cells that resist to treatment and drive cancer relapse.

The impact of PRL receptor (PRLR) signaling on breast and prostate tumorigenesis is supported by strong experimental, clinical and epidemiological evidence. Our current focus in this field involves the dysregulation of prostate stem/progenitor cells in contexts of PRLR hyper-signaling. These ‘primitive’ cells are considered to be tumor-initiating cells while their androgen-independence suggests they may also participate in cancer relapse (escape to treatment). Besides this core project (Aim #1), we also investigate the mechanisms underlying prostate tumor promotion by calcium signaling (Aim #2) and the role of interferon (IFN) signaling in breast cancer response versus resistance to treatment (Aim #3).

Research objectives

  1. Determine the identity of castration-tolerant prostate cell(s), decipher their regulation downstream of PRLR signaling, and identify new actionable targets to prevent cancer relapse
  2. Elucidate the vicious circle involving calcium signaling and tissue inflammation in prostate cancer progression.
  3. Decipher cell-autonomous IFN-related responses to treatment of breast cancer cells to develop strategies preventing cancer relapse.

5 main publications

  • Bernichtein S, et al. (2017) Vitamin D3 prevents calcium-induced progression of early-stage prostate tumors by counteracting TRPC6 and calcium sensing receptor upregulation. Cancer Res.77(2):355-365
  • Chakhtoura Z, et al. (2016) Gain-of-function Prolactin Receptor Variants Are Not Associated With Breast Cancer and Multiple Fibroadenoma Risk. J Clin Endocrinol Metab 101(11):4449-4460.
  • Gaston J, et al. (2016) Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents. Oncotarget, 7(47):77205-77224
  • Goffin, V., and Touraine, P. (2015). The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications. Expert Opin Ther Targets 19, 1229-1244
  • Sackmann-Sala L, et al. (2014) Prolactin-Induced Prostate Tumorigenesis Links Sustained Stat5 Signaling with the Amplification of Basal/Stem Cells and Emergence of Putative Luminal Progenitors. Am. J. Pathol 184:3105-3119.
Last 30 publications

2017

  • Laget S, Broncy L, Hormigos K, Dhingra DM, BenMohamed F, Capiod T, Osteras M, Farinelli L, Jackson S, Paterlini-Bréchot P. Technical Insights into Highly Sensitive Isolation and Molecular Characterization of Fixed and Live Circulating Tumor Cells for Early Detection of Tumor Invasion. PLoS One. 2017 Jan 6;12(1):e0169427. doi: 10.1371/journal.pone.0169427.
  • Bernichtein S, Pigat N, Barry Delongchamps N, Boutillon F, Verkarre V, Camparo P, Reyes-Gomez E, Méjean A, Oudard SM, Lepicard EM, Viltard M, Souberbielle JC, Friedlander G, Capiod T, Goffin V. Vitamin D3 Prevents Calcium-Induced Progression of Early-Stage Prostate Tumors by Counteracting TRPC6 and Calcium Sensing Receptor Upregulation. Cancer Res. 2017 Jan 15;77(2):355-365.
  • 2016

  • Tang MW, Reedquist KA, Garcia S, Fernandez BM, Codullo V, Vieira-Sousa E, Goffin V, Reuwer AQ, Twickler MT, Gerlag DM, Tak PP. The prolactin receptor is expressed in rheumatoid arthritis and psoriatic arthritis synovial tissue and contributes to macrophage activation. Rheumatology (Oxford). 2016 Dec;55(12):2248-2259.
  • Delongchamps NB, Denjean L, Pigat N, Xylinas E, Pop C, Capiod T, Guidotti J, Goffin V, Bories P. Étude de la prévalence d’expression du variant ARV7 dans une population d’hommes soumis au dépistage du cancer de la prostate. Prog Urol. 2016 Nov;26(13):779-780.
  • Capiod T, Bernichtein S, Pigat N, Boutillon F, Barry Delongchamps N, Souberbielle J, Friedlander G, Goffin V. Effets opposés du calcium et de la vitamine D dans le développement du cancer de la prostate. Prog Urol. 2016 Nov;26(13):777. doi: 10.1016/j.purol.2016.07.218. French. No abstract available.
  • Goffin V, Sackmann Sala L, Menara G, Pélard AG, Boutillon F, Leprévost M, Delongchamps NB, Guidotti J. Découverte d’une nouvelle population de cellules progénitrices luminales prostatiques résistantes à la castration. Prog Urol. 2016 Nov;26(13):776. doi: 10.1016/j.purol.2016.07.216. French. No abstract available.
  • Barry Delongchamps N, Pigat N, Sibony M, Vacherot F, De la Taille A, Verkarre V, Dusaud M, Timsit M, Sackman Sala L, Guidotti J, Capiod T, Goffin V. Voie de signalisation prolactine/STAT5 : vers un nouveau mécanisme de développement de l’hyperplasie bénigne de la prostate ? Prog Urol. 2016 Nov;26(13):730-731.
  • Chakhtoura Z, Laki F, Bernadet M, Cherifi I, Chiche A, Pigat N, Bernichtein S, Courtillot C, Boutillon F, Bièche I, Vacher S, Tanguy ML, Bissery A, Grouthier V, Camparo P, Foretz M, Do Cruzeiro M, Pierre R, Rakotozafy F, Tichet J, Tejedor I, Guidotti JE, Sigal-Zafrani B, Goffin V, Touraine P. Gain-of-function Prolactin Receptor Variants Are Not Associated With Breast Cancer and Multiple Fibroadenoma Risk. J Clin Endocrinol Metab. 2016 Nov;101(11):4449-4460.
  • Gaston J, Cheradame L, Yvonnet V, Deas O, Poupon MF, Judde JG, Cairo S, Goffin V. Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents. Oncotarget. 2016 Nov 22;7(47):77205-77224.
  • Meléndez García R, Arredondo Zamarripa D, Arnold E, Ruiz-Herrera X, Noguez Imm R, Baeza Cruz G, Adán N, Binart N, Riesgo-Escovar J, Goffin V, Ordaz B, Peña-Ortega F, Martínez-Torres A, Clapp C, Thebault S. Prolactin protects retinal pigment epithelium by inhibiting sirtuin 2-dependent cell death. EBioMedicine. 2016 May;7:35-49.
  • Patil M, Henry M, Goffin V, Akopian A. (300) Prolactin regulates sensory neurons in a female-specific manner at their peripheral and central terminals and not at their cell bodies. J Pain. 2016 Apr;17(4S):S51. doi: 10.1016/j.jpain.2016.01.207. No abstract available.
  • 2015

  • Goffin V, Touraine P. The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications. Expert Opin Ther Targets. 2015 Sep;19(9):1229-44.
  • Grachev P, Li XF, Goffin V, O'Byrne KT. Hypothalamic Prolactin Regulation of Luteinizing Hormone Secretion in the Female Rat. Endocrinology. 2015 Aug;156(8):2880-92.
  • Bernichtein S, Pigat N, Capiod T, Boutillon F, Verkarre V, Camparo P, Viltard M, Méjean A, Oudard S, Souberbielle JC, Friedlander G, Goffin V. High milk consumption does not affect prostate tumor progression in two mouse models ofbenign and neoplastic lesions. PLoS One. 2015 May 4;10(5):e0125423. doi:10.1371/journal.pone.0125423. eCollection 2015. PubMed PMID: 25938513; PubMedCentral PMCID: PMC4418739.
  • Sackmann-Sala L, Angelergues A, Boutillon F, d'Acremont B, Maidenberg M, Oudard S, Goffin V. Human and murine prostate basal/stem cells are not direct targets of prolactin. Gen Comp Endocrinol. 2015 Apr 15. pii: S0016-6480(15)00097-0. doi: 10.1016/j.ygcen.2015.04.007. [Epub ahead of print] PubMed PMID: 25888939.
  • Bernichtein S, Pigat N, Camparo P, Latil A, Viltard M, Friedlander G, Goffin V. Anti-inflammatory properties of Lipidosterolic extract of Serenoa repens (Permixon®) in a mouse model of prostate hyperplasia. Prostate. 2015 May;75(7):706-22.
  • Zhang C, Nygaard M, Haxholm GW, Boutillon F, Bernadet M, Hoos S, England P, Broutin I, Kragelund BB, Goffin V. A Residue Quartet in the Extracellular Domain of the Prolactin Receptor Selectively Controls Mitogen-activated Protein Kinase Signaling. J Biol Chem. 2015 May 8;290(19):11890-904.
  • Zhang C, Cherifi I, Nygaard M, Haxholm GW, Bogorad RL, Bernadet M, England P, Broutin I, Kragelund BB, Guidotti JE, Goffin V. Residue 146 regulates prolactin receptor folding, basal activity and ligand-responsiveness: potential implications in breast tumorigenesis. Mol Cell Endocrinol. 2015 Feb 5;401:173-88.
  • Sackmann-Sala L, Guidotti JE, Goffin V. Minireview: prolactin regulation of adult stem cells. Mol Endocrinol. 2015 May;29(5):667-81.
  • Beurrier S, Peyromaure M, Belas O, Barry Delongchamps N. [Are the UroLift(®) implants an alternative for the treatment of benign prostatic hyperplasia? Short-term results and predictive factors of failure]. Prog Urol. 2015 Jul;25(9):523-9.
  • Haxholm GW, Nikolajsen LF, Olsen JG, Fredsted J, Larsen FH, Goffin V, Pedersen SF, Brooks AJ, Waters MJ, Kragelund BB. Intrinsically disordered cytoplasmic domains of two cytokine receptors mediate conserved interactions with membranes. Biochem J. 2015 Jun 15;468(3):495-506.
  • 2014

  • Sackmann-Sala L, Chiche A, Mosquera-Garrote N, Boutillon F, Cordier C, Pourmir I, Pascual-Mathey L, Kessal K, Pigat N, Camparo P, Goffin V. Prolactin-induced prostate tumorigenesis links sustained Stat5 signaling with the amplification of basal/stem cells and emergence of putative luminal progenitors. Am J Pathol. 2014 Nov;184(11):3105-19.
  • Sackmann-Sala L, Goffin V. Prolactin-induced prostate tumorigenesis. Adv Exp Med Biol. 2015;846:221-42.
  • Borowiec AS, Bidaux G, Tacine R, Dubar P, Pigat N, Delcourt P, Mignen O, Capiod T. Are Orai1 and Orai3 channels more important than calcium influx for cell proliferation? Biochim Biophys Acta. 2014 Feb;1843(2):464-72.
  • Borowiec AS, Bidaux G, Pigat N, Goffin V, Bernichtein S, Capiod T. Calcium channels, external calcium concentration and cell proliferation. Eur J Pharmacol. 2014 Sep 15;739:19-25.
  • Collin de l'Hortet A, Zerrad-Saadi A, Prip-Buus C, Fauveau V, Helmy N, Ziol M, Vons C, Billot K, Baud V, Gilgenkrantz H, Guidotti JE. GH administration rescues fatty liver regeneration impairment by restoring GH/EGFR pathway deficiency. Endocrinology. 2014 Jul;155(7):2545-54.
  • Merlen G, Gentric G, Celton-Morizur S, Foretz M, Guidotti JE, Fauveau V, Leclerc J, Viollet B, Desdouets C. AMPKα1 controls hepatocyte proliferation independently of energy balance by regulating Cyclin A2 expression. J Hepatol. 2014 Jan;60(1):152-9.
  • Neradugomma NK, Subramaniam D, Tawfik OW, Goffin V, Kumar TR, Jensen RA, Anant S. Prolactin signaling enhances colon cancer stemness by modulating Notch signaling in a Jak2-STAT3/ERK manner. Carcinogenesis. 2014 Apr;35(4):795-806.
  • 2013

  • Ferraris J, Bernichtein S, Pisera D, Goffin V. Use of prolactin receptor antagonist to better understand prolactin regulation of pituitary homeostasis. Neuroendocrinology. 2013;98(3):171-9.
  • Fourcade G, Colombo BM, Grégoire S, Baeyens A, Rachdi L, Guez F, Goffin V, Scharfmann R, Salomon BL. Fetal pancreas transplants are dependent on prolactin for their development and prevent type 1 diabetes in syngeneic but not allogeneic mice. Diabetes. 2013 May;62(5):1646-55.
  • Permanent researcher
    Nicolas Barry Delongchamps
    Professor Researcher
    +33 (0)1 58 41 27 83
    Thierry Capiod
    Researcher
    +33 (0)1 40 61 53 25
    Vincent Goffin
    Researcher
    +33 (0)1 72 60 63 68
    Jacques-Emmanuel Guidotti
    Researcher
    +33 (0)1 72 60 63 77
    Ahmed Hamai
    Researcher
    +33 (0)1 72 60 64 77
    Maryam Mehrpour
    Researcher
    +33 (0)1 72 60 64 80
    Patrizia Paterlini-Brechot
    Professor Researcher
    +33 (0)1 72 60 64 61
    Michael Peyromaure-Debord-Broca
    Professor Researcher
    Philippe Touraine
    Professor Researcher
    +33 (0)1 42 16 02 54
    Permanent engineer
    Natascha Pigat
    -
    +33 (0)1 72 60 63 67
    PhD
    Manon Baures
    PhD Student
    0140615324
    Laura Cheradame
    PhD Student
    +33 (0)1 72 60 63 67
    Emma Cosialls
    PhD Student
    Leila Dos Santos
    PhD Student
    Laura Garrido Castillo
    PhD Student
    Student
    Olivier Knoerr
    -
    Robin Veaux
    -
    Address

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    Support(s)
    HRH Princess Caroline of Hanover, who through the Princess Grace Foundation, already supports medical research and anything that helps to relieve the sick children in France and around the world, has agreed to commit to our side so that our Center of Molecular medicine continues to meet the current challenges and fight diseases, and in particular the ones affecting children.

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