ErbB-2 signaling in advanced prostate cancer progression and potential therapy

Abstract

Currently, prostate cancer (PCa) remains the most commonly diagnosed solid tumor and the second leading cause of cancer-related deaths in US men. Most of these deaths are attributed to the development of castration-resistant (CR) PCa. ErbB-2 and ErbB family members have been demonstrated to contribute to the progression of this lethal disease. In this review, we focus on updating the role of ErbB-2 in advanced PCa progression and its regulation, including its regulation via ligand activation, miRNAs and protein phosphorylation. We also discuss its downstream signaling pathways, including AKT, ERK1/2 and STATs, involved in advanced PCa progression. Additionally, we evaluate the potential of ErbB-2, focusing on its protein hyper-phosphorylation status, as a biomarker for aggressive PCa as well as the effectiveness of ErbB-2 as a target for the treatment of CR PCa via a multitude of approaches, including orally available inhibitors, intratumoral expression of cPAcP, vaccination and immunotherapy.

Keywords: ErbB-2; castration-resistant prostate cancer; ErbB-2-targeting therapies; ErbB-2 regulation.

Figure 1.. Structure of the ErbB Receptor

ErbB receptors transmembrane proteins with both intracellular and extracellular domains. The extracellular domain is composed of four sub-domains, including two leucine-rich sub-domains (I and III) for ligand binding and two cysteine-rich sub-domains (II and IV) for dimerization with activated ErbB members. Inactivated ErbB receptors remain in the ‘closed’ conformation, while ErbB-2 is constitutively in the ‘open’ confirmation. The dimerization with other ligand-bound ErbB family members will lead to activate ErbB-2 for signaling. Intracellularly, ErbB receptors have a juxtamembrane region, a kinase domain, and a cytoplasmic tail that is regulated by tyrosine phosphorylation.

Figure 2.. ErbB-2 Regulation by Ligands and Proteins

There are numerous ligands that can activate ErbB-1/3/4. ErbB-3 can only be activated by NRG1/2, while ErbB-4 is activated upon binding of NRG3/4, HB-EGF, EPR and BTC. ErbB-1 has the most numerous known ligands including HB-EGF, BTC, EPR, EGF, TGF-α, EPG, and AREG. ErbB-2 can be activated via CXCR4 when this protein is bound to its ligand, CXCL12, via Src kinase. Interestingly, ErbB-2 can also promote the activation of CXCR4 as well. Negative regulators of ErbB-2 include microRNA miR-331-3p and cPAcP. PAcP, like other protein tyrosine phosphatases, can be inactivated by ROS and is a downstream of oxidase p66Shc.

Figure 3.. ErbB-2 Downstream Targets to Promote PCa Tumorigenicity

ErbB-2 can regulate numerous signaling pathways in the cell to positively influence cell survival, migration and proliferation. ErbB-2 tyrosine phosphorylation of Y703 or Y845 can activate STATs, which promote AR nuclear translocation and transcription of survival and proliferative genes. ErbB-2 can also activate the Ras-Raf-MEK-ERK pathway upon Y1139 or Y1221/Y1222 phosphorylation to promote proliferation and migration via Grb2 or Shc, respectively. Additionally, ErbB-2 Y920 phosphorylation can induce phosphorylation of PI3K to promote AKT activation via phosphorylation of PIP2 to PIP3 to enhance PCa proliferation and survival. The PI3K/AKT pathway can be inhibited by both PTEN and cPAcP.