Abstract 1973: RNA splicing events may be related to breast cancer prevention

Abstract

Abstract Pregnancy produces a protective effect against breast cancer in women who had their first full term pregnancy (FTP) in their middle twenties. Gene expression profiling of breast biopsies from healthy postmenopausal women revealed up-regulation of genes related to cell adhesion, differentiation, chromatin remodeling and RNA splicing in parous (P) compared to nulliparous (NP) women (Belitskaya-Levy I et al. Cancer Prev Res 2011; Peri S et al. BMC medical genomics 2012). Due to the role of alternative splicing in gene regulation and diseases, we performed RNA-sequencing of 8 P and 8 NP breast biopsies from postmenopausal women free of disease. Alternative splicing events were identified through the Multivariate Alternative Transcript Splicing Software (MATS) and considered statistically significant when FDR were less than 5%. We evaluated the differences between P and NP of five types of splicing: mutually exclusive exon, alternative 5′ splice site, alternative 3′ splice site, skipped exon and retained intron. These last two types had the higher number of statistically significant events different between P and NP. We found 244 skipped exon events, of which 119 events were present in the NP women and 125 were in the P group. Ninety-five retained intron (RI) events were found; of interest is that in P women we found 21 events, while in the NP, 74 RI events were found. RI events were selected for further examination because these events can either be splicing errors or a form of gene expression regulation, which indicate the genes have lower expression and/or, they produce lower quantities of functional proteins. Several of the genes containing RI belong to PI3K-Akt signaling and spliceosome pathways. Gene ontology (GO) analysis revealed that those genes with higher levels of RI in the NP breast enriched mainly GO terms related to RNA processing and splicing. This is in agreement with our previous gene expression results, in which genes involved in RNA processing and splicing were down-regulated in the NP women. Alternative splicing disproportionately affecting important pathways such as PI3K-Akt, spliceosome and other genes involved in mRNA processing in NP women may explain their higher risk for breast cancer. These findings suggest that post-transcriptional regulation is a key element in the differences between the breast of parous and nulliparous women and their lifetime breast cancer risk. Accumulative knowledge of the mechanisms responsible for the protective effect induced by FTP can lead us to the development of agents to protect women with higher breast cancer risk, or can lead us to targets for therapeutic purposes. (The sample collection was supported by Avon Foundation for Women Breast Cancer Research Program grant 02-2010-117 and the RNA-sequencing by NIH core grant CA06927 to Fox Chase Cancer Center). Citation Format: Julia Santucci-Pereira, Sandy Weng, Michael Slifker, Maria Barton, Jose Russo. RNA splicing events may be related to breast cancer prevention. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1973. doi:10.1158/1538-7445.AM2015-1973