At the crossroads: EGFR and PTHrP signaling in cancer-mediated diseases of bone

Abstract

The epidermal growth factor receptor is a well-established cancer therapeutic target due to its stimulation of proliferation, motility, and resistance to apoptosis. Recently, additional roles for the receptor have been identified in growth of metastases. Similar to development, metastatic spread requires signaling interactions between epithelial-derived tumor cells and mesenchymal derivatives of the microenvironment. This necessitates reactivation of developmental signaling molecules, including the hypercalcemia factor parathyroid hormone-related protein. This review covers the variations of epidermal growth factor receptor signaling in cancers that produce bone metastases, regulation of parathyroid hormone-related protein, and evidence that the two molecules drive cancer-mediated diseases of bone.

Fig. 1

EGF and ligand-independent EGFR signaling. a Schematic of EGFR dimer induced by EGF biding. Sites of cytoplasmic tyrosine (Y) phosphorylation are indicated, as are cytosolic effector proteins that bind to these phosphorylated tyrosine residues and some of the effector signaling pathways. b Schematic of potential ligand-independent EGFR signaling induced by mutations and oxidation. The major effector pathways stimulated by these forms of EGFR signaling are indicated

Fig. 2

Ligand-dependent EGFR trafficking and degradation. a Schematic of EGFR internalization and trafficking after binding ligands that have high affinity for the receptor within endosomes. HB-EGF, BTC, and EGF lead to degradation of the receptor in the lysosome. However, the receptor remains phosphorylated and appears to be associated with signaling effector proteins, both in the early endosome and when it is on the external membrane of the multivesicular body. b Schematic of EGFR internalization and trafficking after binding ligands that have low affinity for the receptor within endosomes. TGFα EREG and EPGN induce internalization, but within the endosome, the ligand dissociates and the dimer comes apart, permitting the receptor to be rapidly recycled to the plasma membrane. However, the receptor does not remain phosphorylated and does not appear to extensively signal from internal compartments. Once back on the plasma membrane, the ligand can be rapidly reengaged and signal again

Fig. 3

EGFR activation of PTHrP gene expression. The effector proteins and pathways downstream of the receptor shown to control the P3-PTHrP promoter are illustrated

Fig. 4

ETS factor binding in the region of PTHrP gene. ChIP-seq data using antibodies to the indicated factors are shown aligned to a genomic region (hg18, chr12:27,968,000–28,098,000) surrounding the PTHLH (PTHrP) gene [145, 153]. Antibodies to endogenous ETS1 and GABPA assayed these ETS proteins in a cell line derived from normal prostate (RWPE-1). An anti-FLAG antibody detected FLAG-ERG and FLAG-ETV1 exogenously expressed in RWPE-1 cells. Antibodies recognizing endogenous ETV4 (oncogenic ETS) and JUND (AP-1 subunit) were used for ChIP in PC3 prostate cancer cells (derived from a bone metastasis). H3K4Me1 and H3K4Me3 are histone marks that correlate with enhancer and promoter regions, respectively [202]. Histone methylation data are shown as an overlay from multiple cell types and is from the ENCODE Project, displayed using the UCSC genome browser [203]. A dashed gray line represents the PTHrP P3 core promoter and a solid gray line represents the potential −54 kb enhancer