Genomic signature of parity in the breast of premenopausal women.

ABSTRACT

BACKGROUND: Full-term pregnancy (FTP) at an early age confers long-term protection against breast cancer. Previously, we reported that a FTP imprints a specific gene expression profile in the breast of postmenopausal women. Herein, we evaluated gene expression changes induced by parity in the breast of premenopausal women. METHODS: Gene expression profiling of normal breast tissue from 30 nulliparous (NP) and 79 parous (P) premenopausal volunteers was performed using Affymetrix microarrays. In addition to a discovery/validation analysis, we conducted an analysis of gene expression differences in P vs. NP women as a function of time since last FTP. Finally, a laser capture microdissection substudy was performed to compare the gene expression profile in the whole breast biopsy with that in the epithelial and stromal tissues. RESULTS: Discovery/validation analysis identified 43 differentially expressed genes in P vs. NP breast. Analysis of expression as a function of time since FTP revealed 286 differentially expressed genes (238 up- and 48 downregulated) comparing all P vs. all NP, and/or P women whose last FTP was less than 5 years before biopsy vs. all NP women. The upregulated genes showed three expression patterns (1) transient genes upregulated after FTP but whose expression levels returned to NP levels. These genes were mainly related to immune response, specifically activation of T cells. (2) Long-term changing genes upregulated following FTP, whose expression levels decreased with increasing time since FTP but did not return to NP levels. These were related to immune response and development. (3) Long-term constant genes that remained upregulated in parous compared to nulliparous breast, independently of time since FTP. These were mainly involved in development/cell differentiation processes, and also chromatin remodeling. Lastly, we found that the gene expression in whole tissue was a weighted average of the expression in epithelial and stromal tissues. CONCLUSIONS: Genes transiently activated by FTP may have a role in protecting the mammary gland against neoplastically transformed cells through activation of T cells. Furthermore, chromatin remodeling and cell differentiation, represented by the genes that are maintained upregulated long after the FTP, may be responsible for the lasting preventive effect against breast cancer.