Defining the genomic signature of the parous breast

Abstract

BackgroundIt is accepted that a woman's lifetime risk of developing breast cancer after menopause is reduced by early full term pregnancy and multiparity. This phenomenon is thought to be associated with the development and differentiation of the breast during pregnancy.MethodsIn order to understand the underlying molecular mechanisms of pregnancy induced breast cancer protection, we profiled and compared the transcriptomes of normal breast tissue biopsies from 71 parous (P) and 42 nulliparous (NP) healthy postmenopausal women using Affymetrix Human Genome U133 Plus 2.0 arrays. To validate the results, we performed real time PCR and immunohistochemistry.ResultsWe identified 305 differentially expressed probesets (208 distinct genes). Of these, 267 probesets were up- and 38 down-regulated in parous breast samples; bioinformatics analysis using gene ontology enrichment revealed that up-regulated genes in the parous breast represented biological processes involving differentiation and development, anchoring of epithelial cells to the basement membrane, hemidesmosome and cell-substrate junction assembly, mRNA and RNA metabolic processes and RNA splicing machinery. The down-regulated genes represented biological processes that comprised cell proliferation, regulation of IGF-like growth factor receptor signaling, somatic stem cell maintenance, muscle cell differentiation and apoptosis.ConclusionsThis study suggests that the differentiation of the breast imprints a genomic signature that is centered in the mRNA processing reactome. These findings indicate that pregnancy may induce a safeguard mechanism at post-transcriptional level that maintains the fidelity of the transcriptional process.

Phosphoproteins in extracellular vesicles as candidate markers for breast cancer

“…As a demonstration that PRM can be used to initially verify candidate phosphoproteins, we selected four phosphoproteins: Ral GTPase-activating protein subunit alpha-2 (RALGAPA2), cGMP-dependent protein kinase1 (PKG1), tight junction protein 2 (TJP2), and nuclear transcription factor, X box-binding protein 1 (NFX1). These four proteins showed significant phosphorylation up-regulation in patients with cancer, were previously reported as phosphoproteins, and have been implicated in multiple breast cancer studies (23)(24)(25)(26).…”

Prevention of Breast Cancer Could Be a Consequence of Pregnancy: A Review

“…The genomic profile of nulliparous and parous women in the premenopausal and postmenopausal period has shown that there are genes which are only activated during the first five years after pregnancy that may contribute to the increased risk experienced by certain women after pregnancy [28,47,48,72]. At the same time pregnancy induces a long lasting genomic signature that starts after pregnancy, explaining its preventive effect.…”

“…The morphological, physiological and genomic changes resulting from pregnancy and hormonally-induced differentiation of the breast and their influence on breast cancer risk have been addressed above and in the literature [43][44][45][46][47][48]. The observations that during the postmenopausal years the breasts of both parous and nulliparous women contain predominately Lob 1, and the fact that nulliparous women are at higher risk of developing breast cancer than parous women, indicate that Lob 1 in these two groups of women either differ biologically, or exhibit different susceptibility to carcinogenesis [46].…”

“…The observed chromatin changes in parous epithelial cells are complemented by the expression of genes related to increasing cell adhesion, such as NRXN1, DSC3. COL27A1, PNN, COL4A6, LAMC2, COL7A1, COL16A1, and LAMA3, and differentiation, that include MGP KRT5 GATA3 and LAMA3 [28,48].…”

A Breast Tissue Protein Expression Profile Contributing to Early Parity-Induced Protection Against Breast Cancer

“…It is also our understanding that this is the first study to assess parity-related changes in normal human breast tissue stratified according to early and late parity, as well as, nulliparity. Many prior studies have assessed changes at the transcript level in parous versus nulliparous populations [4,19,21,22]. The study design we have implemented here is critical for assessing changes in the mammary gland that truly play a role in parity-related breast cancer protection.…”