Introduction Cancer is a devastating disease; however, several therapeutic advances have recently been made, wherein EGFR and its family members have emerged as useful biomarkers and therapeutic targets. EGFR, a transmembrane glycoprotein is a member of the ERBB receptor tyrosine kinase superfamily. EGFR binds to its cognate ligand EGF, which further induces tyrosine phosphorylation and receptor dimerization with other family members leading to enhanced uncontrolled proliferation. Several anti-EGFR therapies such as monoclonal antibodies and tyrosine kinase inhibitors have been developed, which has enabled clinicians to identify and treat specific patient cohorts. Areas covered In this review, the basic mechanism of EGFR activation and the role of EGFR signaling in cancer progression, has been covered. Furthermore, current developments made towards targeting the EGFR signaling pathway for the treatment of epithelial cancers and a summary of the various anti-EGFR therapeutic agents that are currently in use, has also been made. Expert opinion EGFR signaling is a part of a complex network that has been the target of effective cancer therapies. However, further understanding of the system is required to develop an effective anticancer regiment. A combination therapy comprising of an anti-EGFR and a chemotherapeutic/chemopreventive agent will exhibit a multi-pronged approach that can be developed into a highly attractive and specific molecular oriented remedy.

MUC16 (CA125) belongs to a family of high-molecular weight O-glycosylated proteins known as mucins. While MUC16 is well known as a biomarker in ovarian cancer, its expression pattern in pancreatic cancer (PC), the fourth leading cause of cancer related deaths in the United States, remains unknown. The aim of our study was to analyze the expression of MUC16 during the initiation, progression and metastasis of PC for possible implication in PC diagnosis, prognosis and therapy. In this study, a microarray containing tissues from healthy and PC patients was used to investigate the differential protein expression of MUC16 in PC. MUC16 mRNA levels were also measured by RT-PCR in the normal human pancreatic, pancreatitis, and PC tissues. To investigate its expression pattern during PC metastasis, tissue samples from the primary pancreatic tumor and metastases (from the same patient) in the lymph nodes, liver, lung and omentum from Stage IV PC patients were analyzed. To determine its association in the initiation of PC, tissues from PC patients containing pre-neoplastic lesions of varying grades were stained for MUC16. Finally, MUC16 expression was analyzed in 18 human PC cell lines. MUC16 is not expressed in the normal pancreatic ducts and is strongly upregulated in PC and detected in pancreatitis tissue. It is first detected in the high-grade pre-neoplastic lesions preceding invasive adenocarcinoma, suggesting that its upregulation is a late event during the initiation of this disease. MUC16 expression appears to be stronger in metastatic lesions when compared to the primary tumor, suggesting a role in PC metastasis. We have also identified PC cell lines that express MUC16, which can be used in future studies to elucidate its functional role in PC. Altogether, our results reveal that MUC16 expression is significantly increased in PC and could play a potential role in the progression of this disease.

MUC16/CA125 is a tumor marker currently used in clinics for the follow-up of patients with ovarian cancer. However, MUC16 expression is not entirely restricted to ovarian malignancies and has been reported in other cancers including breast cancer. Although it is well established as a biomarker, function of MUC16 in cancer remains to be elucidated. In the present study, we investigated the role of MUC16 in breast cancer and its underlying mechanisms. Interestingly, our results showed that MUC16 is overexpressed in breast cancer tissues whereas not expressed in non-neoplastic ducts. Further, stable knockdown of MUC16 in breast cancer cells (MDA MB 231 and HBL100) resulted in significant decrease in the rate of cell growth, tumorigenicity and increased apoptosis. In search of a mechanism for breast cancer cell proliferation we found that MUC16 interacts with the ezrin/radixin/moesin domain-containing protein of Janus kinase (JAK2) as demonstrated by the reciprocal immunoprecipitation method. These interactions mediate phosphorylation of STAT3 (Tyr705), which might be a potential mechanism for MUC16-induced proliferation of breast cancer cells by a subsequent co-transactivation of transcription factor c-Jun. Furthermore, silencing of MUC16 induced G2/M arrest in breast cancer cells through downregulation of Cyclin B1 and decreased phosphorylation of Aurora kinase A. This in turn led to enhanced apoptosis in the MUC16-knockdown breast cancer cells through Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated extrinsic apoptotic pathway with the help of c-Jun N-terminal kinase signaling. Collectively, our results suggest that MUC16 has a dual role in breast cancer cell proliferation by interacting with JAK2 and by inhibiting the apoptotic process through downregulation of TRAIL.

Aberrant expression of mucins is associated with cancer development and metastasis. An overexpression of few mucins contributes to oncogenesis by enhancing cancer cell growth and providing constitutive survival signals. This review focuses on the importance of mucins both in the normal bronchial epithelial cells and the malignant tumors of the lung and their contribution in the diagnosis and prognosis of lung cancer patients. During lung cancer progression, mucins either alone or through their interaction with many receptor tyrosine kinases mediate cell signals for growth and survival of cancer cells. Also, stage-specific expression of certain mucins, like MUC1, is associated with poor prognosis from lung cancer. Thus, mucins are emerging as attractive targets for developing novel therapeutic approaches for lung cancer. Several strategies targeting mucin expression and function are currently being investigated to control lung cancer progression.

MUC16 is a high-molecular-weight glycoprotein that is expressed by the various epithelial cell surfaces of the human body to protect the cell layer from a myriad of insults. It is the largest mucin known to date, with an ∼22,152 aa sequence. Structurally, MUC16 is characterized into 3 distinct domains: the amino terminal, the tandem repeat, and the carboxyl terminal domain, with each domain having unique attributes. The extracellular portion of MUC16 is shed into the bloodstream and serves as a biomarker for diagnosing and monitoring patients with cancer; however, its functional role in cancer is yet to be elucidated. Several factors contribute to this challenge, which include the large protein size; the extensive glycosylation that the protein undergoes, which confers functional heterogeneity; lack of specific antibodies that detect the unique domains of MUC16; and the existence of splicing variants. Despite these limitations, MUC16 has been established as a molecule of significant application in cancer. Hence, in this review, we discuss the various aspects of MUC16, which include its discovery, structure, and biological significance both in benign and malignant conditions with an attempt to dissect its functional relevance