Pregnancy-induced chromatin remodeling in the breast of postmenopausal women.
Early pregnancy and multiparity are known to reduce the risk of women to develop breast cancer at menopause. Based on the knowledge that the differentiation of the breast induced by the hormones of pregnancy plays a major role in this protection, this 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 noncoding 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.
Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. J_Russo@fccc.edu
Jose
J
Russo
Julia
J
Santucci-Pereira
Ricardo López
RL
de Cicco
Fathima
F
Sheriff
Patricia A
PA
Russo
Suraj
S
Peri
Michael
M
Slifker
Eric
E
Ross
Maria Luiza S
ML
Mello
Benedicto C
BC
Vidal
Ilana
I
Belitskaya-Lévy
Alan
A
Arslan
Anne
A
Zeleniuch-Jacquotte
Pal
P
Bordas
Per
P
Lenner
Janet
J
Ahman
Yelena
Y
Afanasyeva
Goran
G
Hallmans
Paolo
P
Toniolo
Irma H
IH
Russo
D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D001940:Breast / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010298:Parity / Q000235:genetics; D017698:Postmenopause / Q000235:genetics*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015415:Biomarkers; D012333:RNA, Messenger