Embryonic Programs in Cancer and Metastasis-Insights From the Mammary Gland

Abstract

Cancer is characterized as a reversion of a differentiated cell to a primitive cell state that recapitulates, in many aspects, features of embryonic cells. This review explores the current knowledge of developmental mechanisms that are essential for embryonic mouse mammary gland development, with a particular focus on genes and signaling pathway components that are essential for the induction, morphogenesis, and lineage specification of the mammary gland. The roles of these same genes and signaling pathways in mammary gland or breast tumorigenesis and metastasis are then summarized. Strikingly, key embryonic developmental pathways are often reactivated or dysregulated during tumorigenesis and metastasis in processes such as aberrant proliferation, epithelial-to-mesenchymal transition (EMT), and stem cell potency which affects cellular lineage hierarchy. These observations are in line with findings from recent studies using lineage tracing as well as bulk- and single-cell transcriptomics that have uncovered features of embryonic cells in cancer and metastasis through the identification of cell types, cell states and characterisation of their dynamic changes. Given the many overlapping features and similarities of the molecular signatures of normal development and cancer, embryonic molecular signatures could be useful prognostic markers for cancer. In this way, the study of embryonic development will continue to complement the understanding of the mechanisms of cancer and aid in the discovery of novel therapeutic targets and strategies.

Keywords: breast cancer; embryonic development; mammary gland; metastasis; molecular signatures.

FIGURE 1

Modes by which the embryonic mammary gland may contribute to breast cancer development. (A) Reactivation of embryonic mammary gland genes or signaling pathways may promote cancer development. (B) Exposure to carcinogens may remodel the postnatal mammary gland and increase breast cancer risk. (C) Embryonic mammary gland cells may contribute to the stem cell pool in the postnatal mammary gland which may be cells of origin of cancer. Note: a representative MR is depicted, however, each mode could be plausibly applied to MRs in other stages of development. Figure created with BioRender.

FIGURE 2

Canonical WNT/β-catenin signaling in the embryonic mammary gland. In the absence of WNT (left, OFF state), cytoplasmic β-catenin is targeted to the destruction complex comprising AXIN, APC, GSK3β and CK1 where it is phosphorylated. Phosphorylated β-catenin is ubiquitinated by the E3 ubiquitin ligase β-TrCP, which targets β-catenin for proteasomal degradation. WNT target genes are repressed by Groucho and histone deacetylases (HDACs). LRP4 and its potential ligand, WISE/SOSTDC1 inhibits WNT signaling. In the presence of WNT ligand (right, ON state), a receptor complex forms between FZD and LRP5/6. DVL recruitment by FZD leads to LRP5/6 phosphorylation and AXIN recruitment. Consequently, degradation of β-catenin is disrupted, allowing β-catenin to accumulate in the nucleus where it functions as a co-activator of LEF1/TCF to promote the transcription of target genes. Genes highlighted in red denote those that give rise to aberrant embryonic mammary gland phenotypes when deleted or overexpressed. P denotes phosphorylation events after overexpressed. Figure created with BioRender.

FIGURE 3

Signaling pathways in the embryonic mammary gland. Cartoon depicting major signaling pathways that are critical during embryonic mammary gland development. (A) Hedgehog signaling. Although Hh ligands are expressed in the MRs, Hedgehog signaling is in the inactivated state. GLI is maintained in the repressor form to repress the transcription of Hh target genes. (B) FGF signaling. FGF10 binding to its main receptor, FGFR2B triggers receptor dimerization, phosphorylation and the activation of diverse downstream pathways. (C) IGF1R signaling. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosine phosphorylation of multiple signaling adapter proteins including, the insulin receptor substrates (IRS1/2). (D) PTHRP signaling. PTHRP binding to the G-coupled receptor PTHR1 activates AC and PLC downstream signaling. (E) BMP signaling. Binding of ligand to the receptor complex stimulates BMPR autophosphorylation and phosphorylation of downstream substrates. BMP4 may interact with PTHRP signaling to facilitate epithelial-mesenchymal cross talk. (F) EDA-EDAR signaling. EDA binding to EDAR triggers downstream NF-kB signaling. (G) NRG3-ERBB4 signaling. NRG binding triggers receptor dimerization and activation of receptor tyrosine kinase domain and downstream signaling. (H) NOTCH signaling. Ligand binding triggers the cleavage of N1ICD which activates downstream signaling. (I) Hormone signaling. Binding of hormones such as estrogen or progesterone to their cognate hormone receptor (HR) promotes internalization of the hormone-receptor complex. Homo- or heterodimer formation ensues followed by translocation into the nucleus and binding to DNA response elements and transcription or repression of target genes. Only relevant components of each signaling pathway in embryonic mammary gland development are depicted. Genes highlighted in red denote genes that give rise to aberrant embryonic mammary gland phenotypes when deleted or overexpressed. P denotes phosphorylation events. Figure created with BioRender.

FIGURE 4

Similarities of genes or signaling pathways critical in embryonic mammary gland development and processes in breast cancer. (A) Key stages in embryonic mammary gland development and genes and their associated pathways involved in the respective stages. For MR-specific developmental processes that are regulated by relevant genes and signaling pathways, please refer to main text. (B,C,D) Processes that are linked to tumorigenesis and metastasis and mediated by the same genes or signaling pathways important for embryonic mammary gland development. Genes in the same signaling pathway are coded in the same colour. Figure created with BioRender.