Abstract
Epidemiologic studies have established that pregnancy has a bidirectional, time-dependent effect on breast cancer risk; a period of elevated risk is followed by a long-term period of protection. The purpose of the present study was to determine whether pregnancy and involution are associated with gene expression changes in the normal breast, and whether such changes are transient or persistent. We examined the expression of a customized gene set in normal breast tissue from nulliparous, recently pregnant (0-2 years since pregnancy), and distantly pregnant (5-10 years since pregnancy) age-matched premenopausal women. This gene set included breast cancer biomarkers and genes related to immune/inflammation, extracellular matrix remodeling, angiogenesis, and hormone signaling. Laser capture microdissection and RNA extraction were done from formalin-fixed paraffin-embedded reduction mammoplasty and benign biopsy specimens and analyzed using real-time PCR arrays containing 59 pathway-specific and 5 housekeeping genes. We report 14 of 64 (22%) of the selected gene set to be differentially regulated (at P < 0.05 level) in nulliparous versus parous breast tissues. Based on gene set analysis, inflammation-associated genes were significantly upregulated as a group in both parous groups compared with nulliparous women (P = 0.03). Moreover, parous subjects had significantly reduced expression of estrogen receptor alpha (ERalpha, ESR1), progesterone receptor (PGR), and ERBB2 (Her2/neu) and 2-fold higher estrogen receptor-beta (ESR2) expression compared with nulliparous subjects. These initial data, among the first on gene expression in samples of normal human breast, provide intriguing clues about the mechanisms behind the time-dependent effects of pregnancy on breast cancer risk.
Highlights
The existence of a link between pregnancy and breast cancer was observed centuries ago, when it was noted that nuns had elevated breast cancer risk [1]
This observation led to the hypothesis that pregnancy is protective against breast cancer [2], which was subsequently supported by numerous epidemiologic analyses [3, 4]. One outcome of these studies was the finding that the protective effect is not immediate and that there is a transient increase in breast cancer risk in the years following pregnancy [5,6,7,8]
Validation studies We performed preliminary studies to show the validity of our approach to gene expression measurement in archival formalin-fixed paraffin-embedded (FFPE) tissues
Summary
The existence of a link between pregnancy and breast cancer was observed centuries ago, when it was noted that nuns had elevated breast cancer risk [1] This observation led to the hypothesis that pregnancy is protective against breast cancer [2], which was subsequently supported by numerous epidemiologic analyses [3, 4]. One outcome of these studies was the finding that the protective effect is not immediate and that there is a transient increase in breast cancer risk in the years following pregnancy [5,6,7,8]. It seems likely that several processes, each with its own temporal dynamics and downstream effects on cancer incidence, may be operating simultaneously in breast tissue after pregnancy
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