Abstract 3672: Defining the genomic signature of the parous breast

Abstract

Abstract Epidemiological data have consistently shown that a pregnancy early in life confer mothers lifetime protection against breast cancer, which is enhanced by subsequent pregnancies. Previous studies have demonstrated that the protection conferred by pregnancy is mediated by the differentiation of the breast, which is expressed as a specific genomic profile detectable in breast cells of postmenopausal parous women that serves as a biomarker indicative of reduced cancer risk. For further confirming these observations we designed a multidisciplinary study for determining whether the pattern of gene expression differed between nulliparous and parous postmenopausal women from an ethnically homogeneous population residing in Norrbotten County, Sweden; the study was approved by the IRB/Ethical Board of the University of Umeå, Sweden. Volunteer women from 50-69 years of age, belonging to one of the following categories based on reproductive history: parous (G≥1/P≥1), nulligravida nullipara (G0/P0) or gravida nullipara (G≥1/P0). The subjects signed an informed consent to participate in the study and donated core needle biopsies (CNB) of breast. CNB were taken from the upper outer quadrant of the breast and divided for 70% ethanol fixation for histopathological analysis and RNA extraction for subsequent genomic analysis. Total RNA was isolated using the Qiagen Allprep RNA/DNA Mini Kit. RNA quantity and quality were determined and the GeneChip Expression 3’-Amplification Two-Cycle cDNA Synthesis Kit (Affymetrix, Santa Clara, CA) was used to prepare the cRNA for hybridization; samples were hybridized to Affymetrix HG_U133 Plus 2.0 oligonucleotide arrays; 71 parous and 42 nulliparous satisfied quality control thresholds based on standard Affymetrix quality control measures. Probesets for which the proportion of Present calls was less than 75% in both samples were filtered out. A variance filter was also applied, removing all probesets whose variance across all samples fell below the first quartile, remaining 18,694 probesets for further analysis using both a p-value of 0.001 from the empirical Bayes moderated t-statistics, and a minimum log2 fold-change of 0.3 threshold as criteria of significance. Two hundred and eight genes were found to be differentially expressed between parous and nulliparous women. Gene ontology and pathway analyses revealed enrichment of biological processes related to regulation of transcription, RNA splicing, cell cycle control, adhesion and differentiation. IGF-like growth factor signaling and somatic stem cell maintenance were significantly downregulated. These results demonstrated that the breast of parous postmenopausal women exhibits a transcriptomic profile that differs from that of nulliparous women, representing a genomic signature induced by full term pregnancy that is indicative of breast differentiation. Work supported by Avon Foundation Women Breast Cancer Research Program grant 02-2008-034. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3672. doi:10.1158/1538-7445.AM2011-3672