HER2 and EGFR Overexpression Support Metastatic Progression of Prostate Cancer to Bone

Abstract

Activation of the epidermal growth factor receptors EGFR (ErbB1) and HER2 (ErbB2) drive the progression of multiple cancer types through complex mechanisms that are still not fully understood. In this study, we report that HER2 expression is elevated in bone metastases of prostate cancer independently of gene amplification. An examination of HER2 and NF-κB receptor (RANK) coexpression revealed increased levels of both proteins in aggressive prostate tumors and metastatic deposits. Inhibiting HER2 expression in bone tumor xenografts reduced proliferation and RANK expression while maintaining EGFR expression. In examining the role of EGFR in tumor-initiating cells (TIC), we found that EGFR expression was required for primary and secondary sphere formation of prostate cancer cells. EGFR expression was also observed in circulating tumor cells (CTC) during prostate cancer metastasis. Dual inhibition of HER2 and EGFR resulted in significant inhibition of tumor xenograft growth, further supporting the significance of these receptors in prostate cancer progression. Overall, our results indicate that EGFR promotes survival of prostate TIC and CTC that metastasize to bone, whereas HER2 supports the growth of prostate cancer cells once they are established at metastatic sites.

Prognostic markers in salivary gland cancer and their impact on survival

“…The poor results of treatment for malignant SGC has given rise to an ongoing search for novel, personalized therapeutic approaches. In many cancers, overexpression of certain proteins has been shown to play a crucial role in cancer pathogenesis and disease progression . For example, in prostate cancer, there is substantial evidence for the overexpression of AR .…”

“…In many cancers, overexpression of certain proteins has been shown to play a crucial role in cancer pathogenesis and disease progression. 9,10 For example, in prostate cancer, there is substantial evidence for the overexpression of AR. 11 Although only limited data are available in SGC, the studies published to date suggest that, similar to prostate cancer, AR is the most commonly expressed receptor in these tumors.…”

GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer

“…5,6 Therefore, investigations of novel therapeutic target molecules outside of AR signaling pathways are needed to develop new therapeutic strategies for CRPC and progressive prostate cancer. Day et al 7 reported that epithelial cell growth factor (EGF) and its receptor (EGF-R) are expressed in prostate cancer tissue and that expression levels of these proteins correlate with survival rate. Furthermore, other growth factors such as vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF) are related to prostate cancer progression.…”

Altered conformational landscape and dimerization dependency underpins the activation of EGFR by α C– β 4 loop insertion mutations

“…M any human cancers are caused by the accumulation of somatic mutations in oncogenes that confer selective growth advantage. The epidermal growth factor receptor (EGFR) kinase is one such oncogene that is mutationally activated in many human cancers, in particular lung cancer (1)(2)(3)(4). Cancer genome sequencing studies have revealed numerous genomic alterations in EGFR, including point mutations, deletions, and insertions (5)(6)(7).…”