Role of lobular involution in pregnancy-associated breast cancer.
Authors: Asztalos S , Gann PH , Hayes MK , Nonn L , Beam CA , Wiley EL , Tonetti DA 
Published: December 2010

Abstract #5038

Introduction: Epidemiological studies have shown that women of all ages experience a transient increase in the risk of developing breast cancer following pregnancy. Furthermore, breast cancers detected soon after a completed pregnancy have a worse prognosis than those detected at more distant intervals. One explanatory hypothesis supported by animal studies suggests that molecular events associated with mammary gland involution, namely inflammation, extracellular matrix (ECM) remodeling and angiogenesis stimulate growth and metastasis (Schedin, P., Nat Rev Cancer 2006). Since no equivalent research has been done on human tissues, the present study compares the expression of a panel of genes in non-malignant human breast tissue obtained from nulliparous and recently pregnant women.&#x2028; Patients and Methods: Women ≤ 45 years of age who had undergone reduction mammoplasty or a negative excision biopsy were eligible for the study, and were categorized as either nulliparous or pregnant within 2 years. Twenty nulliparous and 13 patients with recent pregnancy (&lt;2 years) were identified. Lobular structures were isolated from formalin-fixed paraffin embedded tissues using LCM, followed by RNA extraction and cDNA synthesis. Genes of interest were preamplified linearly, followed by real time PCR. We chose 59 genes involved in the processes of inflammation, ECM remodeling or angiogenesis. A small number of breast cancer prognostic genes were also included. We compared gene expression between patient groups using 2-way ANOVA controlling for sample type and the average linkage method for unsupervised clustering.&#x2028; Results: Clustering analysis failed to show evidence for coordinated upregulation of these genes in the recent pregnancy group. However, 11 genes were differentially regulated between the two groups at the P&lt; 0.05 level. Notably, two immunoglobulin genes, IGKC and IGHA1, were overexpressed and the collagen gene COL1A1 was repressed in the recent pregnancy group, in agreement with published animal studies. Interestingly, expression of ERα, PR and Her2/neu was relatively repressed in recently pregnant subjects, whereas ERβ was upregulated.&#x2028; Conclusions: This is the first report to address a novel potential mechanism for pregnancy-associated breast cancer (PABC) by examining gene expression in human breast tissues. Evidence for differential expression of a number of genes involved in inflammation/ECM in recently pregnant vs. nulliparous women is consistent with the hypothesis that these processes might contribute to the etiology or progression of PABC. However, repression of ERα, PR, and Her2/neu and upregulation of ERβ following pregnancy supports the reported protective effect of pregnancy against breast cancer. We are expanding the number of patients, including a group with a longer interval after pregnancy and also comparing gene expression in breast cancers from nulliparous vs. recently pregnant patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5038.