MEN1 silencing triggers the dysregulation of mTORC1 and MYC pathways in ER+ breast cancer cells

in Endocrine-Related Cancer
Authors:
Razan Abou Ziki Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France

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Romain Teinturier Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France

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Yakun Luo Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France

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https://orcid.org/0000-0002-9644-5025
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Catherine Cerutti Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, CNRS UMR5242, Ecole Normale Supérieure de Lyon, Lyon, France

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Jean-Marc Vanacker Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, CNRS UMR5242, Ecole Normale Supérieure de Lyon, Lyon, France

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Coralie Poulard Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France

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Thomas Bachelot Department of Medical Oncology, Centre Léon Bérard, Lyon, France

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Mona Diab-Assaf Faculty of Sciences II, Lebanese University Fanar, Beirut, Lebanon

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Isabelle Treilleux Département de Biopathologie, Centre Léon Bérard, Lyon, France

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Chang Xian Zhang Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France

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Muriel Le Romancer Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France

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https://orcid.org/0000-0002-8491-4015

Correspondence should be addressed to I Treilleux or C X Zhang: isabelle.treilleux@lyon.unicancer.fr or chang.zhang@lyon.unicancer.fr

*(R Abou Ziki, R Teinturier and Y Luo contributed equally to this work)

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Menin, encoded by the MEN1 gene, has been identified as a critical factor regulating ESR1 transcription, playing an oncogenic role in ER+ breast cancer (BC) cells. Here, we further dissected the consequences of menin inactivation in ER+ BC cells by focusing on factors within two major pathways involved in BC, mTOR and MYC. MEN1 silencing in MCF7 and T-47D resulted in an increase in phosphor-p70S6K1, phosphor-p85S6K1 and phosphor-4EBP1 expression. The use of an AKT inhibitor inhibited the activation of S6K1 and S6RP triggered by MEN1 knockdown (KD). Moreover, MEN1 silencing in ER+ BC cells led to increased formation of the eIF4E and 4G complex. Clinical studies showed that patients with menin-low breast cancer receiving tamoxifen plus everolimus displayed a trend toward better overall survival. Importantly, MEN1 KD in MCF7 and T-47D cells led to reduced MYC expression. ChIP analysis demonstrated that menin bound not only to the MYC promoter but also to its 5’ enhancer. Furthermore, E2-treated MEN1 KD MCF7 cells displayed a decrease in MYC activation, suggesting its role in estrogen-mediated MYC transcription. Finally, expression data mining in tumors revealed a correlation between the expression of MEN1 mRNA and that of several mTORC1 components and targets and a significant inverse correlation between MEN1 and two MYC inhibitory factors, MYCBP2 and MYCT1, in ER+ BC. The current work thus highlights altered mTORC1 and MYC pathways after menin inactivation in ER+ BC cells, providing insight into the crosstalk between menin, mTORC1 and MYC in ER+ BC.

 

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  • Bertolino P, Tong WM, Galendo D, Wang ZQ & Zhang CX 2003 Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1. Molecular Endocrinology 17 18801892. (https://doi.org/10.1210/me.2003-0154)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bièche I, Laurendeau I, Tozlu S, Olivi M, Vidaud D, Lidereau R & Vidaud M 1999 Quantitation of MYC gene expression in sporadic breast tumors with a real-time reverse transcription-PCR assay. Cancer Research 59 27592765.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bosch A, Li Z, Bergamaschi A, Ellis H, Toska E, Prat A, Tao JJ, Spratt DE, Viola-Villegas NT & Castel P et al.2015 PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Science Translational Medicine 7 283ra51. (https://doi.org/10.1126/scitranslmed.aaa4442)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brès V, Yoshida T, Pickle L & Jones KA 2009 SKIP interacts with c-Myc and menin to promote HIV-1 tat transactivation. Molecular Cell 36 7587. (https://doi.org/10.1016/j.molcel.2009.08.015)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Castaneda CA, Cortes-Funes H, Gomez HL & Ciruelos EM 2010 The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer. Cancer Metastasis Reviews 29 751759. (https://doi.org/10.1007/s10555-010-9261-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cheng ASL, Jin VX, Fan M, Smith LT, Liyanarachchi S, Yan PS, Leu YW, Chan MWY, Plass C & Nephew KP et al.2006 Combinatorial analysis of transcription factor partners reveals recruitment of c-MYC to estrogen receptor-alpha responsive promoters. Molecular Cell 21 393404. (https://doi.org/10.1016/j.molcel.2005.12.016)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chu J, Cargnello M, Topisirovic I & Pelletier J 2016 Translation initiation factors: reprogramming protein synthesis in cancer. Trends in Cell Biology 26 918933. (https://doi.org/10.1016/j.tcb.2016.06.005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dai X, Li T, Bai Z, Yang Y, Liu X, Zhan J & Shi B 2015 Breast cancer intrinsic subtype classification, clinical use and future trends. American Journal of Cancer Research 5 29292943.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dermit M, Casado P, Rajeeve V, Wilkes EH, Foxler DE, Campbell H, Critchlow S, Sharp TV, Gribben JG & Unwin R et al.2017 Oxidative stress downstream of mTORC1 but not AKT causes a proliferative defect in cancer cells resistant to PI3K inhibition. Oncogene 36 27622774. (https://doi.org/10.1038/onc.2016.435)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dreijerink KM, Mulder KW, Winkler GS, Höppener JW, Lips CJ & Timmers HT 2006 Menin links estrogen receptor activation to histone H3K4 trimethylation. Cancer Research 66 49294935. (https://doi.org/10.1158/0008-5472.CAN-05-4461)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dreijerink KM, Goudet P, Burgess JR, Valk GD & International Breast Cancer in MEN1 Study Group 2014 Breast-cancer predisposition in multiple endocrine neoplasia type 1. New England Journal of Medicine 371 583584. (https://doi.org/10.1056/NEJMc1406028)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dreijerink KMA, Groner AC, Vos ESM, Font-Tello A, Gu L, Chi D, Reyes J, Cook J, Lim E & Lin CY et al.2017a Enhancer-mediated oncogenic function of the menin tumor suppressor in breast cancer. Cell Reports 18 23592372. (https://doi.org/10.1016/j.celrep.2017.02.025)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dreijerink KMA, Timmers HTM & Brown M 2017b Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1. Endocrine-Related Cancer 24 T135T145. (https://doi.org/10.1530/ERC-17-0281)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ghoncheh M, Pournamdar Z & Salehiniya H 2016 Incidence and mortality and epidemiology of breast cancer in the world. Asian Pacific Journal of Cancer Prevention 17 4346. (https://doi.org/10.7314/apjcp.2016.17.s3.43)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Imachi H, Murao K, Dobashi H, Bhuyan MM, Cao X, Kontani K, Niki S, Murazawa C, Nakajima H & Kohno N et al.2010 Menin, a product of the MENI gene, binds to estrogen receptor to enhance its activity in breast cancer cells: possibility of a novel predictive factor for tamoxifen resistance. Breast Cancer Research and Treatment 122 395407. (https://doi.org/10.1007/s10549-009-0581-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jackson HW, Fischer JR, Zanotelli VRT, Ali HR, Mechera R, Soysal SD, Moch H, Muenst S, Varga Z & Weber WP et al.2020 The single-cell pathology landscape of breast cancer. Nature 578 615620. (https://doi.org/10.1038/s41586-019-1876-x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL & Choti MA et al.2011 DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331 11991203. (https://doi.org/10.1126/science.1200609)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jones N, Bonnet F, Sfar S, Lafitte M, Lafon D, Sierankowski G, Brouste V, Banneau G, Tunon de Lara C & Debled M et al.2013 Comprehensive analysis of PTEN status in breast carcinomas. International Journal of Cancer 133 323334. (https://doi.org/10.1002/ijc.28021)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kan Z, Ding Y, Kim J, Jung HH, Chung W, Lal S, Cho S, Fernandez-Banet J, Lee SK & Kim SW et al.2018 Multi-omics profiling of younger Asian breast cancers reveals distinctive molecular signatures. Nature Communications 9 17251725. (https://doi.org/10.1038/s41467-018-04129-4)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y & Pietenpol JA 2011 Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. Journal of Clinical Investigation 121 27502767. (https://doi.org/10.1172/JCI45014)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li H, Liu X, Wang Z, Lin X, Yan Z, Cao Q, Zhao M & Shi K 2017a MEN1/Menin regulates milk protein synthesis through mTOR signaling in mammary epithelial cells. Scientific Reports 7 5479. (https://doi.org/10.1038/s41598-017-06054-w)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li S, Shen Y, Wang M, Yang J, Lv M, Li P, Chen Z & Yang J 2017b Loss of PTEN expression in breast cancer: association with clinicopathological characteristics and prognosis. Oncotarget 8 3204332054. (https://doi.org/10.18632/oncotarget.16761)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Luo Y, Vlaeminck-Guillem V, Baron S, Dallel S, Zhang CX & Le Romancer M 2021 MEN1 silencing aggravates tumorigenic potential of AR-independent prostate cancer cells through nuclear translocation and activation of JunD and β-catenin. Journal of Experimental and Clinical Cancer Research 40 270. (https://doi.org/10.1186/s13046-021-02058-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Miller TW, Hennessy BT, González-Angulo AM, Fox EM, Mills GB, Chen H, Higham C, García-Echeverría C, Shyr Y & Arteaga CL 2010 Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. Journal of Clinical Investigation 120 24062413. (https://doi.org/10.1172/JCI41680)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, Martincorena I, Alexandrov LB, Martin S & Wedge DC et al.2016 Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534 4754. (https://doi.org/10.1038/nature17676)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Paplomata E & O’Regan R 2014 The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Therapeutic Advances in Medical Oncology 6 154166. (https://doi.org/10.1177/1758834014530023)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Poulard C, Jacquemetton J, Pham TH & Le Romancer M 2020 Using proximity ligation assay to detect protein arginine methylation. Methods 175 6671. (https://doi.org/10.1016/j.ymeth.2019.09.007)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Schneider CA, Rasband WS & Eliceiri KW 2012 NIH Image to ImageJ: 25 years of image analysis. Nature Methods 9 671675. (https://doi.org/10.1038/nmeth.2089)

  • Seigne C, Auret M, Treilleux I, Bonnavion R, Assade F, Carreira C, Goddard-Léon S, Lavergne E, Chabaud S & Garcia A et al.2013 High incidence of mammary intraepithelial neoplasia development in Men1-disrupted murine mammary glands. Journal of Pathology 229 546558. (https://doi.org/10.1002/path.4146)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shang Y, Hu X, DiRenzo J, Lazar MA & Brown M 2000 Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103 843852. (https://doi.org/10.1016/s0092-8674(0000188-4)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shveygert M, Kaiser C, Bradrick SS & Gromeier M 2010 Regulation of eukaryotic initiation factor 4E (eIF4E) phosphorylation by mitogen-activated protein kinase occurs through modulation of Mnk1-eIF4G interaction. Molecular and Cellular Biology 30 51605167. (https://doi.org/10.1128/MCB.00448-10)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Teinturier R, Abou Ziki R, Kassem L, Luo Y, Malbeteau L, Gherardi S, Corbo L, Bertolino P, Bachelot T & Treilleux I et al.2021a Reduced menin expression leads to decreased ERα expression and is correlated with the occurrence of human luminal B-like and ER-negative breast cancer subtypes. Breast Cancer Research and Treatment 190 389401. (https://doi.org/10.1007/s10549-021-06339-9)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Teinturier R, Luo Y, Decaussin-Petrucci M, Vlaeminck-Guillem V, Vacherot F, Firlej V, Bonnavion R, Abou Ziki R, Gherardi S & Goddard I et al.2021b Men1 disruption in Nkx3.1-deficient mice results in AR low/CD44 + microinvasive carcinoma development with the dysregulated AR pathway. Oncogene 40 11181127. (https://doi.org/10.1038/s41388-020-01589-1)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang C, Mayer JA, Mazumdar A, Fertuck K, Kim H, Brown M & Brown PH 2011a Estrogen induces c-myc gene expression via an upstream enhancer activated by the estrogen receptor and the AP-1 transcription factor. Molecular Endocrinology 25 15271538. (https://doi.org/10.1210/me.2011-1037)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang Y, Ozawa A, Zaman S, Prasad NB, Chandrasekharappa SC, Agarwal SK & Marx SJ 2011b The tumor suppressor protein menin inhibits AKT activation by regulating its cellular localization. Cancer Research 71 371382. (https://doi.org/10.1158/0008-5472.CAN-10-3221)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang H, Li W, Wang Q, Wang X, Li F, Zhang C, Wu L, Long H, Liu Y & Li X et al.2012 Glucose-mediated repression of menin promotes pancreatic β-cell proliferation. Endocrinology 153 602611. (https://doi.org/10.1210/en.2011-1460)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation