Abstract
Full-term pregnancy at an early age confers long-term protection against breast cancer. Published data shows a specific transcriptomic profile controlling chromatin remodeling that could play a relevant role in the pregnancy-induced protection. This process of chromatin remodeling, induced by the breast differentiation caused by the first full-term pregnancy, has mainly been measured by the expression level of genes individually considered. However, genes equally expressed during the process of chromatin remodeling may behave differently in their interaction with other genes. These changes at the gene cluster level could constitute an additional dimension of chromatin remodeling and therefore of the pregnancy-induced protection. In this research, we apply Information and Graph Theories, Differential Co-expression Network Analysis, and Multiple Regression Analysis, specially designed to examine structural and informational aspects of data sets, to analyze this question. Our findings demonstrate that, independently of the changes in the gene expression at the individual level, there are significant changes in gene–gene interactions and gene cluster behaviors. These changes indicate that the parous breast, through the process of early full-term pregnancy, generates more modules in the networks, with higher density, and a genomic structure performing additional and more complex functions than those found in the nulliparous breast.
Highlights
Full-term pregnancy at an early age confers long-term protection against breast cancer
As early as the 1700s, it was observed that increased breast cancer incidence and mortality were associated with nulliparity, a fact reported by Bernardino Ramazzini, who attributed the phenomenon to the childlessness of nuns in Italian convents[2]
We have provided evidence supporting that early pregnancy changes the genomic signature causing a differentiation of the lobular structures of the parous breast from those of the nulliparous one[13,15,16]
Summary
Full-term pregnancy at an early age confers long-term protection against breast cancer. As this research team confirmed in the study of Santucci-Pereira and c olleagues[24], the identified transcriptomic changes induced by early FFTP were closely associated with the activation of genes controlling chromatin remodeling, and the expression of Histone 3 at lysine 9 and 27, with the morphological manifestation of an increase in heterochromatin formation that remained in the menopausal breast. This finding is in concordance with the pivotal role played by chromatin remodeling in determining methylation and gene transcription, identified by 28 and 29and shown in25 for FFTP. This study complements gene-by-gene individual approaches with gene-to-gene cluster approaches: we directly inspect the existence of changes, otherwise ignored, in the behavior of gene clusters associated to FFTP, proving their presence, and identifying networks specific for nulliparous and for parous women, or changing from nulliparous to parous
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