Abstract SY02-03: Decoding RNA splicing: A molecular link between aging, inflammation and cancer

作者：Brittany L. Angarola, Hyeon Gu Kang, Masaru M. Miyano, Maëva Devoucoux, SungHee Park, Rosalyn W. Sayaman, Rachel Gott, Rachel Gott, Jeffrey Chuang, Ron Korstanje, Mark A. LaBarge, Olga A. Anczukow · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.am2026-sy02-03 · 研究领域：RNA Research and Splicing、Ferroptosis and cancer prognosis、Single-cell and spatial transcriptomics

Abstract Aging is a critical risk factor for breast cancer: approximately 80% of cases occur in women over 50. While aging drives the accumulation of somatic mutations and broad alterations in epigenetic, transcriptional, and post-transcriptional programs, the molecular mechanisms linking these changes to breast cancer initiation remain poorly defined. Alternative RNA splicing enables a single gene to produce multiple protein isoforms with distinct biological functions. Although splicing alterations have been implicated in breast cancer and in age-related diseases of non-reproductive tissues, their role in the aging breast has not been characterized. Building on our prior work identifying splicing alterations and their regulators in breast tumors, we now reveal aging-associated isoform changes in mammary epithelial cells using short- and long-read RNA-sequencing. We uncover novel age-related spliced transcripts in both human and mouse tissue and identify concordant shifts in upstream splicing regulators, including oncogenic splicing factors. To dissect cell-type-specific regulation, we integrated single-cell RNA-sequencing, single-nucleus ATAC-sequencing, and spatial transcriptomics in aging mouse mammary tissues, revealing coordinated transcriptomic and epigenomic remodeling across cell types and ages. Finally, by integrating splicing and expression data from human tumors, we demonstrate that select tumor-associated splicing signatures are in fact age-driven, suggesting a me...