Dysregulated Alternative Splicing in Breast Cancer Subtypes of RIF1 and Other Transcripts

TL;DR

This study explores how alternative splicing of RIF1 and other transcripts is dysregulated in breast cancer subtypes, affecting clinical outcomes.

Contribution

The study reveals subtype-specific splicing patterns of RIF1 and links them to prognosis in breast cancer.

Findings

RIF1 expression is altered in colon and lung cancers.

LumA, LumB, and HER2E breast cancers show RIF1 Exon 31 exclusion, favoring RIF1-Short and correlating with poor outcomes.

Basal breast cancer shows exon exclusion but no short-exon bias and inconsistent RIF1 Exon 31 exclusion.

Abstract

Genome instability is a hallmark of cancer, often driven by mutations and altered expression of genome maintenance factors involved in DNA replication and repair. Rap1 Interacting Factor 1 (RIF1) plays a crucial role in genome stability and is implicated in cancer pathogenesis. Cells express two RIF1 splice variants, RIF1-Long and RIF1-Short, which differ in their ability to protect cells from DNA replication stress. Here, we investigate differential expression and splicing of RIF1 in cancer cell lines following replication stress and in patients using matched normal and tumour data from The Cancer Genome Atlas (TCGA). Overall RIF1 expression is altered in several cancer types, with increased transcript levels in colon and lung cancers. RIF1 also exhibits distinct splicing patterns, particularly in specific breast cancer subtypes. In Luminal A (LumA), Luminal B (LumB), and HER2-enriched breast cancers (HER2E), RIF1 Exon 31 tends to be excluded, favouring RIF1-Short expression and correlating with poorer clinical outcomes. These breast cancer subtypes also tend to exclude other short exons, suggesting length-dependent splicing dysregulation. Basal breast cancer also shows exon exclusion, but unlike other subtypes, it shows no short-exon bias. Surprisingly, however, in basal breast cancer, RIF1 Exon 31 is not consistently excluded, which may impact prognosis since RIF1-Long protects against replication stress.

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