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.
Highlights
It is accepted that a woman's lifetime risk of developing breast cancer after menopause is reduced by early full term pregnancy and multiparity
Our results suggest that the differentiation of the breast induced by pregnancy imprints a genomic signature that can be detected in postmenopausal women, contributing to the establishment of the molecular basis of the protection against breast cancer conferred by parity
We found that genes which are pivotal in two biological processes that are critical to the anchoring of epithelial cells to the basement membrane, hemidesmosome and cell-substrate junction assembly, such as keratin 5 (KRT5), LAMA3 and LAMC2, were up-regulated in the P group (Table 1)
Summary
It 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. Epidemiological data from various parts of the world have consistently shown that early full term pregnancy and multiparity are associated with breast cancer risk reduction in postmenopausal women [1,2,3], whereas late pregnancy and nulliparity are associated with increased risk [4]. Our results suggest that the differentiation of the breast induced by pregnancy imprints a genomic signature that can be detected in postmenopausal women, contributing to the establishment of the molecular basis of the protection against breast cancer conferred by parity
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