Abstract
IntroductionCancer is often suggested to result from development gone awry. Links between normal embryonic development and cancer biology have been postulated, but no defined genetic basis has been established. We recently published the first transcriptomic analysis of embryonic mammary cell populations. Embryonic mammary epithelial cells are an immature progenitor cell population, lacking differentiation markers, which is reflected in their very distinct genetic profiles when compared with those of their postnatal descendents.MethodsWe defined an embryonic mammary epithelial signature that incorporates the most highly expressed genes from embryonic mammary epithelium when compared with the postnatal mammary epithelial cells. We looked for activation of the embryonic mammary epithelial signature in mouse mammary tumors that formed in mice in which Brca1 had been conditionally deleted from the mammary epithelium and in human breast cancers to determine whether any genetic links exist between embryonic mammary cells and breast cancers.ResultsSmall subsets of the embryonic mammary epithelial signature were consistently activated in mouse Brca1-/- tumors and human basal-like breast cancers, which encoded predominantly transcriptional regulators, cell-cycle, and actin cytoskeleton components. Other embryonic gene subsets were found activated in non-basal-like tumor subtypes and repressed in basal-like tumors, including regulators of neuronal differentiation, transcription, and cell biosynthesis. Several embryonic genes showed significant upregulation in estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and/or grade 3 breast cancers. Among them, the transcription factor, SOX11, a progenitor cell and lineage regulator of nonmammary cell types, is found highly expressed in some Brca1-/- mammary tumors. By using RNA interference to silence SOX11 expression in breast cancer cells, we found evidence that SOX11 regulates breast cancer cell proliferation and cell survival.ConclusionsSpecific subsets of embryonic mammary genes, rather than the entire embryonic development transcriptomic program, are activated in tumorigenesis. Genes involved in embryonic mammary development are consistently upregulated in some breast cancers and warrant further investigation, potentially in drug-discovery research endeavors.
Highlights
Cancer is often suggested to result from development gone awry
We looked for activation of the embryonic mammary epithelial signature in mouse mammary tumors that formed in mice in which Brca1 had been conditionally deleted from the mammary epithelium and in human breast cancers to determine whether any genetic links exist between embryonic mammary cells and breast cancers
Subsets of the embryonic mammary signatures are activated in Brca1-/- mouse tumors We defined an embryonic mammary signature based on expression profiles of genes found highly expressed within midgestation (E12.5-stage) embryonic epithelium compared with postnatal mammary epithelial cells described in Additional file 2[10,13]
Summary
Cancer is often suggested to result from development gone awry. Links between normal embryonic development and cancer biology have been postulated, but no defined genetic basis has been established. Virchow coined the term “teratoma” to describe tumors containing from reactivation of embryonic developmental programs in postnatal tissues. Many other signaling pathways have been implicated in both embryonic mammary morphogenesis and carcinogenesis, providing support for the contention that neoplastic and immature tissues share important similarities and that organ development and primary tumor formation are likely to be underpinned by common mechanisms [6]. Identified cancer stem cells in skin, gut, and brain are very similar to healthy stem cells responsible for growing and renewing tissue in the body, highlighting the need for further understanding of the normal mammary progenitor cells and their potential links to cancer, as tumors may develop from progenitor-like cells from diverse stages of cellular differentiation [7,8,9]
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