Abstract
BackgroundEpidemiological studies have found that triple-negative breast cancer (TNBC) and TN inflammatory breast cancer (IBC) are associated with lower frequency and duration of breast-feeding compared to non-TNBC and non-TN IBC, respectively. Limited breast-feeding could reflect abrupt or premature involution and contribute to a “primed” stroma that is permissive to the migration of cancer cells typical of IBC. We hypothesized that gene expression related to abrupt mammary gland involution after forced weaning may be enriched in the tissues of IBC patients and, if so, provide a potential correlation between limited breast-feeding and the development of aggressive breast cancer.MethodsWe utilized the Short Time-series Expression Miner (STEM) program to cluster significant signatures from two independent studies that analyzed gene expression at multiple time-points of mouse mammary gland involution. Using 10 significant signatures, we performed gene ontology analysis and gene set enrichment analysis (GSEA) on training and validation sets from human breast cancer gene expression data to identify specific genes that are enriched in IBC compared to non-IBC and in TN compared to non-TN in IBC and non-IBC groups.ResultsExamining the combined data, we identified 10 involution gene clusters (Inv1-10) that share time-dependent regulation after forced weaning. Inv5 was the only cluster significantly enriched in IBC in the training and validation set (nominal p-values <0.05) and only by unadjusted p-values (FDR q-values 0.26 and 0.46 respectively). Eight genes in Inv5 are upregulated in both the training and validation sets in IBC. Combining the training and validation sets, both Inv5 and Inv6 have nominal p-values <0.05 and q-values 0.39 and 0.20, respectively. The time course for both clusters includes genes that change within 12 hours after forced weaning.ConclusionsResults from this in silico study suggest correlation between molecular events during abrupt involution and aggressive breast cancer. Specifically, candidate genes from Inv5 merit functional investigation regarding the role of limited breast-feeding in IBC development.
Highlights
The mammary gland undergoes various stages of development during the embryonic, pubertal, reproductive, and post-reproductive stages of life
Out of 10 gene signatures developed through STEM clustering using data from Clarkson et al [3], we found that no gene signature was significantly enriched in TN subtype versus non-TN subtype in inflammatory breast cancer (IBC) cases at false discovery rate (FDR)
For involution specific signatures reported by Stein et al [4], we did not find any gene signature that was significantly enriched in TN subtype versus non-TN subtype in IBC cases at FDR
Summary
The mammary gland undergoes various stages of development during the embryonic, pubertal, reproductive, and post-reproductive stages of life. Clarkson et al [3] and Stein et al [4] conducted gene expression profiling studies of these changes in the mouse mammary gland with the induction of forced weaning at the peak of lactation. Results of these two studies highlight distinct molecular characteristics between the virgin, pregnant, lactating, and involuting states of the mammary gland. We hypothesized that gene expression related to abrupt mammary gland involution after forced weaning may be enriched in the tissues of IBC patients and, if so, provide a potential correlation between limited breast-feeding and the development of aggressive breast cancer
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