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Article

Genomic Mapping of Splicing-Related Genes Identify Amplifications in LSM1, CLNS1A, and ILF2 in Luminal Breast Cancer

1
Translational Oncology Laboratory, Translational Research Unit, Albacete University Hospital, 02008 Albacete, Spain
2
Centro Regional de Investigaciones Biomédicas, Castilla-La Mancha University (CRIB-UCLM), 02008 Albacete, Spain
3
Molecular Oncology Laboratory, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain
4
Experimental Therapeutics Unit, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain
5
Centro de Investigación Biomédica en Red en Oncología (CIBERONC), 28029 Madrid, Spain
6
Medical Oncology Department, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain
7
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Instituto de Investigación Biomédica de Salamanca (IBSAL), Consejo Superior de Investigaciones Científicas (CSIC) and CIBERONC, 37007 Salamanca, Spain
8
Department of Bioinformatics, Semmelweis University, H-1094 Budapest, Hungary
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2nd Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary
10
TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, H-1117 Budapest, Hungary
*
Authors to whom correspondence should be addressed.
Equal contributors.
Academic Editors: Ion Cristóbal and Marta Rodríguez
Cancers 2021, 13(16), 4118; https://doi.org/10.3390/cancers13164118
Received: 19 July 2021 / Revised: 9 August 2021 / Accepted: 13 August 2021 / Published: 16 August 2021
(This article belongs to the Special Issue Molecular Pathways in Cancers)
The alternative splicing (AS) process is highly relevant, affecting most of the hallmarks of cancer, such as proliferation, angiogenesis, and metastasis. Our study evaluated alterations in 304 splicing-related genes and their prognosis value in breast cancer patients. Amplifications in CLNS1A, LSM1, and ILF2 genes in luminal patients were significantly associated with poor outcome. Downregulation of these genes in luminal cell lines showed an antiproliferative effect. Pharmacological modulation of transcription and RNA regulation is key for the optimal development of therapeutic strategies against key proteins. Administration of a BET inhibitor and BET-PROTAC reduced the expression of these identified genes and displayed a significant antiproliferative effect on these cell models. In conclusion, we describe novel splicing genes amplified in luminal breast tumors that are associated with detrimental prognosis and can be modulated pharmacologically. It opens the door for further studies confirming the effect of these genes in patients treated with BET inhibitors.
Alternative splicing is an essential biological process, which increases the diversity and complexity of the human transcriptome. In our study, 304 splicing pathway-related genes were evaluated in tumors from breast cancer patients (TCGA dataset). A high number of alterations were detected, including mutations and copy number alterations (CNAs), although mutations were less frequently present compared with CNAs. In the four molecular subtypes, 14 common splice genes showed high level amplification in >5% of patients. Certain genes were only amplified in specific breast cancer subtypes. Most altered genes in each molecular subtype clustered to a few chromosomal regions. In the Luminal subtype, amplifications of LSM1, CLNS1A, and ILF2 showed a strong significant association with prognosis. An even more robust association with OS and RFS was observed when expression of these three genes was combined. Inhibition of LSM1, CLNS1A, and ILF2, using siRNA in MCF7 and T47D cells, showed a decrease in cell proliferation. The mRNA expression of these genes was reduced by treatment with BET inhibitors, a family of epigenetic modulators. We map the presence of splicing-related genes in breast cancer, describing three novel genes, LSM1, CLNS1A, and ILF2, that have an oncogenic role and can be modulated with BET inhibitors. View Full-Text
Keywords: splicing pathway; luminal breast cancer; BET inhibitors splicing pathway; luminal breast cancer; BET inhibitors
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Figure 1

MDPI and ACS Style

Noblejas-López, M.d.M.; López-Cade, I.; Fuentes-Antrás, J.; Fernández-Hinojal, G.; Esteban-Sánchez, A.; Manzano, A.; García-Sáenz, J.Á.; Pérez-Segura, P.; la Hoya, M.d.; Pandiella, A.; Győrffy, B.; García-Barberán, V.; Ocaña, A. Genomic Mapping of Splicing-Related Genes Identify Amplifications in LSM1, CLNS1A, and ILF2 in Luminal Breast Cancer. Cancers 2021, 13, 4118. https://doi.org/10.3390/cancers13164118

AMA Style

Noblejas-López MdM, López-Cade I, Fuentes-Antrás J, Fernández-Hinojal G, Esteban-Sánchez A, Manzano A, García-Sáenz JÁ, Pérez-Segura P, la Hoya Md, Pandiella A, Győrffy B, García-Barberán V, Ocaña A. Genomic Mapping of Splicing-Related Genes Identify Amplifications in LSM1, CLNS1A, and ILF2 in Luminal Breast Cancer. Cancers. 2021; 13(16):4118. https://doi.org/10.3390/cancers13164118

Chicago/Turabian Style

Noblejas-López, María d.M., Igor López-Cade, Jesús Fuentes-Antrás, Gonzalo Fernández-Hinojal, Ada Esteban-Sánchez, Aránzazu Manzano, José Á. García-Sáenz, Pedro Pérez-Segura, Miguel d. la Hoya, Atanasio Pandiella, Balázs Győrffy, Vanesa García-Barberán, and Alberto Ocaña. 2021. "Genomic Mapping of Splicing-Related Genes Identify Amplifications in LSM1, CLNS1A, and ILF2 in Luminal Breast Cancer" Cancers 13, no. 16: 4118. https://doi.org/10.3390/cancers13164118

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