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 mechanistic link to preneoplastic progression. Together, these findings define new molecular hallmarks of the aging mammary gland and nominate splicing alterations as novel breast cancer risk factors and candidate targets for early detection, intervention, and prevention. Citation Format: Brittany L. Angarola, Hyeon Gu Kang, Masaru M. Miyano, Maeva Devoucoux, SungHee Park, Rosalyn Sayaman, Rachel Gott, Rachel Gott, Jeffrey Chuang, Ron Korstanje, Mark A. LaBarge, Olga A. Anczukow. Decoding RNA splicing: A molecular link between aging, inflammation and cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr SY02-03.
Angarola et al. (Fri,) studied this question.