Embryonic mammary signature subsets are activated in Brca1 -/- and basal-like breast cancers

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.

Developmental Changes in the in Vitro Activated Regenerative Activity of Primitive Mammary Epithelial Cells

“…The most significant of these is Sox11 , also noted by Spike et al 2012 [8], and identified in a recent comparison of E12.5 mammary rudiments with adult mammary cells [29]. Additional genes of interest that we found are up-regulated in the E18.5 fetal cells include two that encode insulin growth factor 2 mRNA-binding proteins ( Igf2bp1 and Igf2bp3 ), which are let-7 miRNA targets broadly implicated in many tissue growth and metabolism networks operative during development [30].…”

The mammary stem cell hierarchy: a looking glass into heterogeneous breast cancer landscapes

“…While most studies rely on the alignment of the adult human epithelial hierarchy to breast cancer subtype, Spike et al identified a signature from the isolation of the murine embryonic MaSCs, that showed significant enrichment of the fMaSC signature in basal-like and Her2 + tumors (Spike et al 2012). A separate study also demonstrated that embryonic mammary signature subsets were enriched in basal-like breast cancers and those of BRCA1-null murine tumors (Zvelebil et al 2013). Collectively, these data may implicate the potential cell-of-origin for a particular subtype based upon the association with a lineage-restricted gene signature.…”

SLUG: Critical regulator of epithelial cell identity in breast development and cancer

“…72,[89][90][91] Recently, a subset of embryonic mammary epithelial genes was also found to be up-regulated in basal-type tumors; several of theses genes, including BCl11a, GRHL3, PROX1, and SOX11, were previously shown to function as regulators of progenitor cell activity or differentiation. 92 Furthermore, several studies have reported an enrichment of CD24 ¡ /CD44 C breast cancer stem cells (BCSCs) in basal-type tumors. [93][94][95][96] The discovery that basal-type tumors exhibit stem-like features suggests that properties inherent to stem cells, such as increased plasticity and decreased lineage specification, may contribute to the basal tumor phenotype.…”