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, 10 (57), 6021-6037

Splicing Regulatory Factors in Breast Cancer Hallmarks and Disease Progression


Splicing Regulatory Factors in Breast Cancer Hallmarks and Disease Progression

Esmee Koedoot et al. Oncotarget.


By regulating transcript isoform expression levels, alternative splicing provides an additional layer of protein control. Recent studies show evidence that cancer cells use different splicing events to fulfill their requirements in order to develop, progress and metastasize. However, there has been less attention for the role of the complex catalyzing the complicated multistep splicing reaction: the spliceosome. The spliceosome consists of multiple sub-complexes in total comprising 244 proteins or splice factors and 5 associated RNA molecules. Here we discuss the role of splice factors in the oncogenic processes tumors cells need to fulfill their oncogenic properties (the so-called the hallmarks of cancer). Despite the fact that splice factors have been investigated only recently, they seem to play a prominent role in already five hallmarks of cancer: angiogenesis, resisting cell death, sustaining proliferation, deregulating cellular energetics and invasion and metastasis formation by affecting major signaling pathways such as epithelial-to-mesenchymal transition, the Warburg effect, DNA damage response and hormone receptor dependent proliferation. Moreover, we could relate expression of representative genes of four other hallmarks (enabling replicative mortality, genomic instability, avoiding immune destruction and evading growth suppression) to splice factor levels in human breast cancer tumors, suggesting that also these hallmarks could be regulated by splice factors. Since many splice factors are involved in multiple hallmarks of cancer, inhibiting splice factors might provide a new layer of oncogenic control and a powerful method to combat breast cancer progression.

Keywords: RNA sequencing; alternative splicing; breast cancer; hallmarks of cancer; splice factors.

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare that they have no competing interests.


Figure 1
Figure 1. The role of splice factors and their associated pathways in the five hallmarks of cancer.
Core splicing factors are listed in bold. Non-core splicing factors are listed in italic. Adapted from Hanahan and Weinberg, 2011 [21].
Figure 2
Figure 2. Relation of splice factor expression levels to other hallmarks of cancer.
(A) Steps used to link splice factor RNA expression levels to the other hallmarks of cancer. (B) Heatmap displaying the log2 fold change of genome instability markers comparing primary tumor tissue to normal tissue. NER = nucleotide excision repair, DSBR = double strand break repair, BER = base excision repair, DMMR = DNA mismatch repair. (C) Heatmap of log2 fold change of genome instability markers in ten control and hallmark patients comparing normal to primary tumor tissue. (D) Log2 fold change of splice factors in control and hallmark patients comparing normal to primary tumor tissue.

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