Introduction: 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. 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.
Methods: We 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.
Results: Small 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, cellcycle,
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.
Conclusions: Specific 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