Low level of Fibrillarin, a ribosome biogenesis factor, is a new independent marker of poor outcome in breast cancer

Flora Nguyen Van Long; Audrey Lardy-Cleaud; Dimitri Carène; Caroline Rossoni; Frédéric Catez; Paul Rollet; Nathalie Pion; Déborah Monchiet; Agathe Dolbeau; Marjorie Martin; Valentin Simioni; Susan Bray; Doris Le Beherec; Fernanda Mosele; Ibrahim Bouakka; Amélie Colombe-Vermorel; Laetitia Odeyer; Alexandra Diot; Lee B. Jordan; Alastair M. Thompson; Françoise Jamen; Thierry Dubois; Sylvie Chabaud; Stefan Michiels; Isabelle Treilleux; Jean-Christophe Bourdon; David Pérol; Alain Puisieux; Fabrice André; Jean-Jacques Diaz; Virginie Marcel

doi:10.1186/s12885-022-09552-x

Low level of Fibrillarin, a ribosome biogenesis factor, is a new independent marker of poor outcome in breast cancer

Flora Nguyen Van Long, Audrey Lardy-Cleaud, Dimitri Carène, Caroline Rossoni, Frédéric Catez, Paul Rollet, Nathalie Pion, Déborah Monchiet, Agathe Dolbeau, Marjorie Martin, Valentin Simioni, Susan Bray, Doris Le Beherec, Fernanda Mosele, Ibrahim Bouakka, Amélie Colombe-Vermorel, Laetitia Odeyer, Alexandra Diot, Lee B. Jordan, Alastair M. ThompsonFrançoise Jamen, Thierry Dubois, Sylvie Chabaud, Stefan Michiels, Isabelle Treilleux, Jean-Christophe Bourdon, David Pérol, Alain Puisieux, Fabrice André, Jean-Jacques Diaz (Lead / Corresponding author), Virginie Marcel (Lead / Corresponding author)

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Abstract

Background: A current critical need remains in the identification of prognostic and predictive markers in early breast cancer. It appears that a distinctive trait of cancer cells is their addiction to hyperactivation of ribosome biogenesis. Thus, ribosome biogenesis might be an innovative source of biomarkers that remains to be evaluated.

Methods: Here, fibrillarin (FBL) was used as a surrogate marker of ribosome biogenesis due to its essential role in the early steps of ribosome biogenesis and its association with poor prognosis in breast cancer when overexpressed. Using 3,275 non-metastatic primary breast tumors, we analysed FBL mRNA expression levels and protein nucleolar organisation. Usage of TCGA dataset allowed transcriptomic comparison between the different FBL expression levels-related breast tumours.

Results: We unexpectedly discovered that in addition to breast tumours expressing high level of FBL, about 10% of the breast tumors express low level of FBL. A correlation between low FBL mRNA level and lack of FBL detection at protein level using immunohistochemistry was observed. Interestingly, multivariate analyses revealed that these low FBL tumors displayed poor outcome compared to current clinical gold standards. Transcriptomic data revealed that FBL expression is proportionally associated with distinct amount of ribosomes, low FBL level being associated with low amount of ribosomes. Moreover, the molecular programs supported by low and high FBL expressing tumors were distinct.

Conclusion: Altogether, we identified FBL as a powerful ribosome biogenesis-related independent marker of breast cancer outcome. Surprisingly we unveil a dual association of the ribosome biogenesis FBL factor with prognosis. These data suggest that hyper- but also hypo-activation of ribosome biogenesis are molecular traits of distinct tumors.

Original language	English
Article number	526
Pages (from-to)	1-12
Number of pages	12
Journal	BMC Cancer
Volume	22
DOIs	https://doi.org/10.1186/s12885-022-09552-x
Publication status	Published - 11 May 2022

Keywords

Biomarkers/metabolism
Breast Neoplasms/genetics
Chromosomal Proteins, Non-Histone
Female
Humans
RNA, Messenger/genetics
Ribosomes/genetics
rRNA 2’O-ribose methylation complex
Ribosome biogenesis
Fibrillarin
AgNOR
Breast cancer

ASJC Scopus subject areas

Genetics
Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s12885-022-09552-xLicence: CC BY

Final published versionFinal published version, 4.25 MBLicence: CC BY

Cite this

Nguyen Van Long, F., Lardy-Cleaud, A., Carène, D., Rossoni, C., Catez, F., Rollet, P., Pion, N., Monchiet, D., Dolbeau, A., Martin, M., Simioni, V., Bray, S., Le Beherec, D., Mosele, F., Bouakka, I., Colombe-Vermorel, A., Odeyer, L., Diot, A., Jordan, L. B., ... Marcel, V. (2022). Low level of Fibrillarin, a ribosome biogenesis factor, is a new independent marker of poor outcome in breast cancer. BMC Cancer, 22, 1-12. Article 526. https://doi.org/10.1186/s12885-022-09552-x

@article{220598c37ed34fe6933166ce66be4b85,

title = "Low level of Fibrillarin, a ribosome biogenesis factor, is a new independent marker of poor outcome in breast cancer",

abstract = "Background: A current critical need remains in the identification of prognostic and predictive markers in early breast cancer. It appears that a distinctive trait of cancer cells is their addiction to hyperactivation of ribosome biogenesis. Thus, ribosome biogenesis might be an innovative source of biomarkers that remains to be evaluated.Methods: Here, fibrillarin (FBL) was used as a surrogate marker of ribosome biogenesis due to its essential role in the early steps of ribosome biogenesis and its association with poor prognosis in breast cancer when overexpressed. Using 3,275 non-metastatic primary breast tumors, we analysed FBL mRNA expression levels and protein nucleolar organisation. Usage of TCGA dataset allowed transcriptomic comparison between the different FBL expression levels-related breast tumours.Results: We unexpectedly discovered that in addition to breast tumours expressing high level of FBL, about 10% of the breast tumors express low level of FBL. A correlation between low FBL mRNA level and lack of FBL detection at protein level using immunohistochemistry was observed. Interestingly, multivariate analyses revealed that these low FBL tumors displayed poor outcome compared to current clinical gold standards. Transcriptomic data revealed that FBL expression is proportionally associated with distinct amount of ribosomes, low FBL level being associated with low amount of ribosomes. Moreover, the molecular programs supported by low and high FBL expressing tumors were distinct.Conclusion: Altogether, we identified FBL as a powerful ribosome biogenesis-related independent marker of breast cancer outcome. Surprisingly we unveil a dual association of the ribosome biogenesis FBL factor with prognosis. These data suggest that hyper- but also hypo-activation of ribosome biogenesis are molecular traits of distinct tumors.",

keywords = "Biomarkers/metabolism, Breast Neoplasms/genetics, Chromosomal Proteins, Non-Histone, Female, Humans, RNA, Messenger/genetics, Ribosomes/genetics, rRNA 2{\textquoteright}O-ribose methylation complex, Ribosome biogenesis, Fibrillarin, AgNOR, Breast cancer",

author = "{Nguyen Van Long}, Flora and Audrey Lardy-Cleaud and Dimitri Car{\`e}ne and Caroline Rossoni and Fr{\'e}d{\'e}ric Catez and Paul Rollet and Nathalie Pion and D{\'e}borah Monchiet and Agathe Dolbeau and Marjorie Martin and Valentin Simioni and Susan Bray and {Le Beherec}, Doris and Fernanda Mosele and Ibrahim Bouakka and Am{\'e}lie Colombe-Vermorel and Laetitia Odeyer and Alexandra Diot and Jordan, {Lee B.} and Thompson, {Alastair M.} and Fran{\c c}oise Jamen and Thierry Dubois and Sylvie Chabaud and Stefan Michiels and Isabelle Treilleux and Jean-Christophe Bourdon and David P{\'e}rol and Alain Puisieux and Fabrice Andr{\'e} and Jean-Jacques Diaz and Virginie Marcel",

note = "Funding Information: We thank platforms{\textquoteright} staffs that have not been referred as co-authors: Tayside Tissue Bank (TTBD, Dundee, Scotland, UK); CRB Centre L{\'e}on B{\'e}rard (Lyon, France, Dir: Dr S. Tabone-Eglinger); CRCL Microscopy facilities (CRCL, Lyon, France, co-Dir: Dr C. Vanbelle); BioCOS Life Sciences (Bioinformatics, Bengalor, India); English editing (CRCL, Lyon, France, B. Manship). We thank Emilie Lavergne for her help in biostatistics at the beginning of the project. Funding Information: The access to human series, clinical data, statistical analyses and reagents for experiments were funded by PAIR Sein program (RiboTEM: ARC_INCa_LNCC_7625), PLBio program (MARACAS: INCa PLBIO19-178), PRT-K program (EMT-CoNCEPT: INCa PRT K17 2018–024), SIRIC program (INCa-DGOS-Inserm_12563, LyRICAN), Fondation ARC (PJA 20161204686) and Ligue Contre le Cancer Comit{\'e} Is{\`e}re (PME 2017). FNVL was a recipient of a fellowship from Ligue Nationale Contre le Cancer then from Fondation pour la Recherche M{\'e}dicale. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = may,

day = "11",

doi = "10.1186/s12885-022-09552-x",

language = "English",

volume = "22",

pages = "1--12",

journal = "BMC Cancer",

issn = "1471-2407",

publisher = "Springer Verlag",

}

Nguyen Van Long, F, Lardy-Cleaud, A, Carène, D, Rossoni, C, Catez, F, Rollet, P, Pion, N, Monchiet, D, Dolbeau, A, Martin, M, Simioni, V, Bray, S, Le Beherec, D, Mosele, F, Bouakka, I, Colombe-Vermorel, A, Odeyer, L, Diot, A, Jordan, LB, Thompson, AM, Jamen, F, Dubois, T, Chabaud, S, Michiels, S, Treilleux, I, Bourdon, J-C, Pérol, D, Puisieux, A, André, F, Diaz, J-J & Marcel, V 2022, 'Low level of Fibrillarin, a ribosome biogenesis factor, is a new independent marker of poor outcome in breast cancer', BMC Cancer, vol. 22, 526, pp. 1-12. https://doi.org/10.1186/s12885-022-09552-x

TY - JOUR

T1 - Low level of Fibrillarin, a ribosome biogenesis factor, is a new independent marker of poor outcome in breast cancer

AU - Nguyen Van Long, Flora

AU - Lardy-Cleaud, Audrey

AU - Carène, Dimitri

AU - Rossoni, Caroline

AU - Catez, Frédéric

AU - Rollet, Paul

AU - Pion, Nathalie

AU - Monchiet, Déborah

AU - Dolbeau, Agathe

AU - Martin, Marjorie

AU - Simioni, Valentin

AU - Bray, Susan

AU - Le Beherec, Doris

AU - Mosele, Fernanda

AU - Bouakka, Ibrahim

AU - Colombe-Vermorel, Amélie

AU - Odeyer, Laetitia

AU - Diot, Alexandra

AU - Jordan, Lee B.

AU - Thompson, Alastair M.

AU - Jamen, Françoise

AU - Dubois, Thierry

AU - Chabaud, Sylvie

AU - Michiels, Stefan

AU - Treilleux, Isabelle

AU - Bourdon, Jean-Christophe

AU - Pérol, David

AU - Puisieux, Alain

AU - André, Fabrice

AU - Diaz, Jean-Jacques

AU - Marcel, Virginie

N1 - Funding Information: We thank platforms’ staffs that have not been referred as co-authors: Tayside Tissue Bank (TTBD, Dundee, Scotland, UK); CRB Centre Léon Bérard (Lyon, France, Dir: Dr S. Tabone-Eglinger); CRCL Microscopy facilities (CRCL, Lyon, France, co-Dir: Dr C. Vanbelle); BioCOS Life Sciences (Bioinformatics, Bengalor, India); English editing (CRCL, Lyon, France, B. Manship). We thank Emilie Lavergne for her help in biostatistics at the beginning of the project. Funding Information: The access to human series, clinical data, statistical analyses and reagents for experiments were funded by PAIR Sein program (RiboTEM: ARC_INCa_LNCC_7625), PLBio program (MARACAS: INCa PLBIO19-178), PRT-K program (EMT-CoNCEPT: INCa PRT K17 2018–024), SIRIC program (INCa-DGOS-Inserm_12563, LyRICAN), Fondation ARC (PJA 20161204686) and Ligue Contre le Cancer Comité Isère (PME 2017). FNVL was a recipient of a fellowship from Ligue Nationale Contre le Cancer then from Fondation pour la Recherche Médicale. Publisher Copyright: © 2022, The Author(s).

PY - 2022/5/11

Y1 - 2022/5/11

N2 - Background: A current critical need remains in the identification of prognostic and predictive markers in early breast cancer. It appears that a distinctive trait of cancer cells is their addiction to hyperactivation of ribosome biogenesis. Thus, ribosome biogenesis might be an innovative source of biomarkers that remains to be evaluated.Methods: Here, fibrillarin (FBL) was used as a surrogate marker of ribosome biogenesis due to its essential role in the early steps of ribosome biogenesis and its association with poor prognosis in breast cancer when overexpressed. Using 3,275 non-metastatic primary breast tumors, we analysed FBL mRNA expression levels and protein nucleolar organisation. Usage of TCGA dataset allowed transcriptomic comparison between the different FBL expression levels-related breast tumours.Results: We unexpectedly discovered that in addition to breast tumours expressing high level of FBL, about 10% of the breast tumors express low level of FBL. A correlation between low FBL mRNA level and lack of FBL detection at protein level using immunohistochemistry was observed. Interestingly, multivariate analyses revealed that these low FBL tumors displayed poor outcome compared to current clinical gold standards. Transcriptomic data revealed that FBL expression is proportionally associated with distinct amount of ribosomes, low FBL level being associated with low amount of ribosomes. Moreover, the molecular programs supported by low and high FBL expressing tumors were distinct.Conclusion: Altogether, we identified FBL as a powerful ribosome biogenesis-related independent marker of breast cancer outcome. Surprisingly we unveil a dual association of the ribosome biogenesis FBL factor with prognosis. These data suggest that hyper- but also hypo-activation of ribosome biogenesis are molecular traits of distinct tumors.

AB - Background: A current critical need remains in the identification of prognostic and predictive markers in early breast cancer. It appears that a distinctive trait of cancer cells is their addiction to hyperactivation of ribosome biogenesis. Thus, ribosome biogenesis might be an innovative source of biomarkers that remains to be evaluated.Methods: Here, fibrillarin (FBL) was used as a surrogate marker of ribosome biogenesis due to its essential role in the early steps of ribosome biogenesis and its association with poor prognosis in breast cancer when overexpressed. Using 3,275 non-metastatic primary breast tumors, we analysed FBL mRNA expression levels and protein nucleolar organisation. Usage of TCGA dataset allowed transcriptomic comparison between the different FBL expression levels-related breast tumours.Results: We unexpectedly discovered that in addition to breast tumours expressing high level of FBL, about 10% of the breast tumors express low level of FBL. A correlation between low FBL mRNA level and lack of FBL detection at protein level using immunohistochemistry was observed. Interestingly, multivariate analyses revealed that these low FBL tumors displayed poor outcome compared to current clinical gold standards. Transcriptomic data revealed that FBL expression is proportionally associated with distinct amount of ribosomes, low FBL level being associated with low amount of ribosomes. Moreover, the molecular programs supported by low and high FBL expressing tumors were distinct.Conclusion: Altogether, we identified FBL as a powerful ribosome biogenesis-related independent marker of breast cancer outcome. Surprisingly we unveil a dual association of the ribosome biogenesis FBL factor with prognosis. These data suggest that hyper- but also hypo-activation of ribosome biogenesis are molecular traits of distinct tumors.

KW - Biomarkers/metabolism

KW - Breast Neoplasms/genetics

KW - Chromosomal Proteins, Non-Histone

KW - Female

KW - Humans

KW - RNA, Messenger/genetics

KW - Ribosomes/genetics

KW - rRNA 2’O-ribose methylation complex

KW - Ribosome biogenesis

KW - Fibrillarin

KW - AgNOR

KW - Breast cancer

UR - http://www.scopus.com/inward/record.url?scp=85129812521&partnerID=8YFLogxK

U2 - 10.1186/s12885-022-09552-x

DO - 10.1186/s12885-022-09552-x

M3 - Article

C2 - 35545761

SN - 1471-2407

VL - 22

SP - 1

EP - 12

JO - BMC Cancer

JF - BMC Cancer

M1 - 526

ER -

Low level of Fibrillarin, a ribosome biogenesis factor, is a new independent marker of poor outcome in breast cancer

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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