Long noncoding RNAs in the postmenopausal breast and their role in cancer prevention

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Our initial transcriptomic analysis in the normal breast of parous and nulliparous women reveals that long non-coding RNA genes (lncRNAs) such as nuclear paraspeckle assembly transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and X inactive specific transcript (XIST) are up-regulated in the parous breast [Cancer Prev Res 4 1457-1464, 2011, BMC Medical Genomics. 5:46. 2012 and Int. J. Cancer: 131, 1059-1070, 2012]. This novel observation provides a new paradigm in our understanding of the role of lncRNAs in the regulation of transcription and its potential function in pregnancy's preventive effect in reducing the lifetime risk of developing breast cancer. In the present work, we performed RNA sequencing of healthy postmenopausal breast tissue biopsies from 8 parous (P) and 8 nulliparous (NP) women using Illumina TruSeq for the library preparation and Illumina HiSeq 2000 (Illumina Inc., San Diego, CA) for RNA sequencing (RNAseq). The 16 sequenced samples (8P, 8NP) satisfied quality control thresholds. The sequencing results show that 140 genes were differentially expressed in the parous vs. the nulliparous breast tissue with fold change of two and a p-value of 0.05. Also, using t-statistics with p-value less than 0.01 and fold-change of at least two as criteria of significance, we identified 42 differentially expressed lncRNAs between P and NP women. Of these, 21 lncRNAs were up-regulated and 21 were down-regulated. We also identified 10 lncRNAs that show strong Pearson correlation of the differentially expressed lncRNA and its corresponding gene, for example lnc-CDH5-1 (long non-coding CDH5, transcript variant 1) and its corresponding gene CDH5 (cadherin 5, type 2) show a correlation p- value of 0.017 and a correlation estimate of -0.59. These results provide not only novel information on the hormonal regulation of lncRNAs induced by pregnancy in breast cells, but also place lncRNAs as potential key regulators in breast differentiation. These results begin to render a comprehensive picture of the differentiation of the human breast at the transcriptomic level, findings that will lead to the identification of the role played by lncRNAs in the prevention of breast cancer. (The sample collection was supported by Avon Foundation for Women Breast Cancer Research Program grant 02-2010-117 and the RNA sequencing studies by NIH core grant CA06927 to Fox Chase Cancer Center). Citation Format: Maria Barton, Julia Santucci-Pereira, Ricardo Lopez de Cicco, Irma H. Russo, Eric A. Ross, Michael Slifker, Suraj Peri, Pal Bordas, Per Lenner, Goran Hallmans, Paolo Toniolo, Jose Russo. Long noncoding RNAs in the postmenopausal breast and their role in cancer prevention. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1480. doi:10.1158/1538-7445.AM2014-1480