Chromatin Remodeling in the Breast of Parous Women Affects the Window of Susceptibility to Cancer.
Jose Russo, MD, Breast Cancer Research Laboratory, Temple-Fox Chase Cancer Center, Philadelphia, PA
Early pregnancy and multiparity are known to reduce the risk of women to develop breast cancer at menopause. The differentiation of the breast induced by the hormones of pregnancy is thought to play a major role in this protection, so the present work was performed with the purpose of identifying what differentiation-associated molecular changes persist in the breast until menopause. Core needle biopsies (CNB) obtained from the breast of 42 nulliparous (NP) and 71 parous (P) postmenopausal women were analyzed in morphology, immunocytochemistry and gene expression. Whereas in the NP, breast nuclei of epithelial cells were large and euchromatic, in the P breast they were small and hyperchromatic, showing strong methylation of Histone 3 at lysine 9 and 27. Transcriptomic analysis performed using Affymetrix HG_U133 oligonucleotide arrays revealed that in CNB of the P breast there were 267 upregulated probesets that comprised genes controlling chromatin organization, transcription regulation, splicing machinery, mRNA processing, and non-coding elements including XIST. We concluded that the differentiation process induced by pregnancy is centered in chromatin remodeling and in the mRNA processing reactome, both of which emerge as important regulatory pathways. These are indicative of a safeguard step that maintains the fidelity of the transcription process, becoming the ultimate mechanism mediating the protection of the breast conferred by full term pregnancy.
. (Supported by grant 02-2008-034 from the Avon Foundation for Women Breast Cancer Research Program).