Receptor tyrosine kinases (RTKs) in breast cancer: signaling, therapeutic implications and challenges

Abstract

Breast cancer is a multifactorial disease and driven by aberrant regulation of cell signaling pathways due to the acquisition of genetic and epigenetic changes. An array of growth factors and their receptors is involved in cancer development and metastasis. Receptor Tyrosine Kinases (RTKs) constitute a class of receptors that play important role in cancer progression. RTKs are cell surface receptors with specialized structural and biological features which respond to environmental cues by initiating appropriate signaling cascades in tumor cells. RTKs are known to regulate various downstream signaling pathways such as MAPK, PI3K/Akt and JAK/STAT. These pathways have a pivotal role in the regulation of cancer stemness, angiogenesis and metastasis. These pathways are also imperative for a reciprocal interaction of tumor and stromal cells. Multi-faceted role of RTKs renders them amenable to therapy in breast cancer. However, structural mutations, gene amplification and alternate pathway activation pose challenges to anti-RTK therapy.

Keywords: Alternate pathway activation; Angiogenesis; Anti-RTK therapy; Bevacizumab; Brest cancer; Cancer Stem cells; Drug resistance; Lapatinib; Metastasis; Trastuzumab; Tumor microenvironment; Tumor-stroma interaction.

Fig. 1

Structure of prototype of receptor tyrosine kinase and mechanism of activation. Receptor tyrosine kinases (RTKs) have the following structural segments from N- to C-terminal: immunoglobulin folds, transmembrane region, juxtamembrane region, N-lobe, activation loop, C-lobe and cytoplasmic tail. RTKs reside at the plasma membrane as a monomer. Ligand binding crosslinks receptor molecules and induces conformational changes that lead to receptor autophosphorylation and activation. Phosphorylated RTK either serves as a docking site for adaptor proteins (B) or may directly phosphorylate signaling molecules (A). Adaptor proteins or signaling molecules bind to phosphorylated receptor through Src homology 2 (SH2) or phosphotyrosine-binding (PTB) domain. Docked adaptor proteins further transduce signal by phosphorylating other downstream molecules (C, D)

Fig. 2

RTK-regulated signaling in breast cancer progression. VEGFR activates JAK/STAT signaling pathway to induce cancer stem cell phenotype through Myc and Sox2 expression. Mutant p53 induces the expression of VEGFR through the interaction with SWI/SNF complex. EGFR-regulated signaling also plays pivotal role in angiogenesis and metastasis. EGFR regulates the activation of JAK/STAT and MAPK signaling pathway to induce expression of Sox2 and other stem cell markers leading to enrichment of cancer stem cells. EGFR induces Akt phosphorylation to promote inflammation. PDGFR is expressed on stromal cells such as fibroblasts and is a marker of fibroblast activation. PDGFR-regulated STAT activation is involved in regulation of miR-9-mediated differentiation of cancer cells to endothelial cells leading to angiogenesis. FGFR-activated MAPK pathway induces EMT and CSC phenotype. Cooperation between the FGFR and HER2 regulates nuclear translocation of Cyclin D1 leading to enhanced cancer cell proliferation

Fig. 3

RTK signaling in drug resistance. a Conventional chemotherapeutic agents reduce the cancer progression through the inhibition of MAPK/PI3K/Akt signaling axis. Amplification and overexpression of RTKs including EGFR, HER2 and PDGFR reinforce the activation of PI3K/Akt/YB-1/RTK axis to maintain drug resistance; increases the kinase activity and thereby leading to cancer progression, drug efflux and cancer stemness. b Cancer cells exhibit resistance to RTK therapy due to disruption of interaction between drug and receptor or activation of alternate RTK signaling