SRC kinase-mediated signaling pathways and targeted therapies in breast cancer

Abstract

Breast cancer (BC) has been ranked the most common malignant tumor throughout the world and is also a leading cause of cancer-related deaths among women. SRC family kinases (SFKs) belong to the non-receptor tyrosine kinase (nRTK) family, which has eleven members sharing similar structure and function. Among them, SRC is the first identified proto-oncogene in mammalian cells. Oncogenic overexpression or activation of SRC has been revealed to play essential roles in multiple events of BC progression, including tumor initiation, growth, metastasis, drug resistance and stemness regulations. In this review, we will first give an overview of SRC kinase and SRC-relevant functions in various subtypes of BC and then systematically summarize SRC-mediated signaling transductions, with particular emphasis on SRC-mediated substrate phosphorylation in BC. Furthermore, we will discuss the progress of SRC-based targeted therapies in BC and the potential future direction.

Keywords: Breast cancer; SRC kinase; Signaling transduction; Targeted therapy; Tyrosine phosphorylation.

Fig. 1

Schematic overview of the basic structure of SRC protein. SRC protein is mainly composed of seven parts (from N- to C-terminus): SH4 domain, unique domain, SH3 domain, SH2 domain, SH2-kinase linker domain, SH1 domain and the C-­terminal negative regulatory region

Fig. 2

SRC kinase configuration with Tyr530 phosphorylation or Tyr419 phosphorylation, respectively. SRC activity is inhibited when the phosphorylated Y530 at the C­-terminal region binds to the SH2 domain, which will prevent the interaction of substrate proteins with the kinase domain (left panel). Dephosphorylated Y530 will induce the disassociation of the C-­terminal region from the SH2 domain, which allows substrate protein access to the catalytic kinase site in the SH1 domain, and be subsequently phosphorylated by SRC kinase (right panel)

Fig. 3

SRC kinase-mediated phosphorylation and function of membrane proteins in BC. SRC can interact with multiple membrane proteins through tyrosine phosphorylation, including HER family members, TGFβ receptor, AJ components and other transmembrane proteins, to coordinate the signaling transductions and cell proliferation, survival, migration, invasion and metastasis in BC

Fig. 4

SRC kinase-mediated phosphorylation and function of cytoplasmic proteins in BC. SRC can phosphorylate multiple cytoplasmic proteins at tyrosine residues, including FA components, PI3K/AKT signaling components, as well as many protein kinases and proteases, thereby regulating mammary tumorigenesis and metastasis in various BC subtypes

Fig. 5

SRC kinase-mediated phosphorylation and function of nuclear proteins in BC. SRC can directly phosphorylate multiple nuclear proteins, including transcription factors, cell cycle regulators and RNA-binding proteins, thereby coordinating gene expression, cell cycle and BC-related cell behaviors