If so, EGFR methylation may help stratify patients to maximize response to EGFR mAb. review, we describe some of the molecular mechanisms underlying EGFR inhibitor sensitivity and further discuss the possible therapeutic strategies to increase the efficacy of EGFR inhibitors in TNBC. genes [9,10]. and are involved in double-stranded DNA damage repair and play an essential role in DNA PHT-427 integrity. The incidence of breast malignancy in individuals with germline mutations is usually 20-30 times higher than those without the mutations, and 75% of breast cancer patients with mutation turned out to have TNBC [11]. Recently, inhibitors against poly (ADP-ribose) polymerase (PARP) have been shown to induce synthetic lethality in mutated advanced ovarian malignancy. Several other PARP inhibitors are being tested in clinical trials and are expected to receive approval for treatment for patients with TNBC and BLBC. EGFR in human cancers EGFR is usually a receptor tyrosine kinase (RTK) that belongs to the ErbB family, and a transmembrane protein comprising an extracellular ligand binding domain name, transmembrane domain name, and cytoplasmic tyrosine kinase domain name [12-14]. When a ligand binds to the extracellular region of EGFR, the receptor forms a dimer, turning on its kinase activity, followed by autophosphorylation at multiple tyrosine residues in the intracellular region to recruit numerous substrates. The receptor activation promotes cell proliferation, motility, and survival via activation of various downstream signaling pathways, such as Ras-Raf-MEK-ERK, PI3K-AKT-mTOR, and Src-STAT3 [15]. Ligand-activated EGFR molecules are then ubiquitinated, internalized, and isolated in endosomes. You will find two major pathways of internalized EGFR, lysosome-mediated degradation pathway, Rabbit polyclonal to Acinus which transports EGFR to the lysosomes for degradation, and receptor recycling pathway, which sorts EGFR to cell surface again [14,15]. EGFR is also known to translocate into the nucleus, where it is involved in transcriptional regulation, DNA replication, and DNA repair [16]. The gene is frequently mutated or overexpressed lung, colon, head and neck, brain, pancreatic, and breast cancers and promotes tumor progression and drug resistance in these cancers [17-20]. Therefore, EGFR is an attractive drug target, and the inhibitors of EGFR, including TKIs and mAbs, have been developed and some are currently used in the medical center. Overexpression of EGFR in malignancy is usually PHT-427 partly due to gene amplification [21], but the underlying mechanisms are not yet fully comprehended. It has been reported that EGFR degradation through endocytosis is critical for upregulation of EGFR protein in some types of malignancy cells, including breast malignancy cells [22,23]. Moreover, inhibition of BRCA1 has been shown to induce upregulation of EGFR mRNA and protein in breast and ovarian malignancy cells [24,25] even though molecular mechanisms are still uncertain. Because TNBC is usually closely associated with [27] and Rakha [29] reported a frequency of 13% and 37% of EGFR overexpression, respectively, in TNBC using an PHT-427 antibody from Novocastra (2+ to 3+ membranous staining in 10% tumor cells for evaluation). Tan reported a rate of 52% of EGFR overexpression in TNBC using an antibody from Zymed (2+ to 3+ membranous staining in 10% tumor cells) [30]. Using EGFR PharmDx Kit (Dako), which is usually widely used to assess EGFR expression in CRC, Martin have indicated a frequency of 76% of EGFR overexpression in TNBC [31]. EGFR protein overexpression has been detected in 72% of TNBC by EGFR PhrmDx, but a frequency of 11% and 47%, respectively, of EGFR mRNA overexpression and normal expression was also observed in the same study [32], suggesting that protein overexpression in TNBC is usually partly due to post-transcriptional regulation, such as protein stabilization or enhanced recycling. Amplification of gene was observed in 2-24% of TNBC individual tumor tissue samples whereas high polysomy of EGFR gene was reported to be between 8-27% (Table 1) [31,35-38]. Therefore, gene amplification only partly accounts for expression of EGFR protein. Table 1 EGFR protein expression, gene mutations, and copy number in TNBC genes, but the results are controversial (Table 1). Santarpia have documented that this EGFR-activating mutation (L858R) exists in 3.4% of TNBC (4 out of 116) [39]. However, several reports from Europe PHT-427 and Australia.
