Pancreatic cancer is one of the malignant tumors that causes the most deaths in the world due to its late clinical manifestations 1. Adenocarcinoma of the pancreas has a poor long-term survival. Late clinical manifestations of this disease lead to advanced tumor and metastases, that's why few patients are eligible for surgery. The only treatment that increases the patient's chance of survival is pancreaticoduodenectomy. Extensive studies have been conducted to identify effective and helpful treatment strategies for pancreatic cancer. Until now, therapeutic goals such as chemotherapy have not been very effective 2, 3. New investigations of the effect of different factors such as growth factor receptors against molecular targets in the treatment of several types of cancer have shown promising results such as effects on tumor growth, apoptosis, and metastasis. Anti-human epidermal growth factor receptor (HER or ErbB) agents seem to have promising results in several types of cancer, including gastrointestinal malignancies 4, 5. Among important membranous growth factor receptors, HER-1 as epidermal growth factor receptor (EGFR), HER-2 as c-erbB-2 and HER-3 (c-erbB-3) and HER-4 (cerbB- 4) which contain an extracellular ligand binding domain, a transmembrane region and an intracellular one with protein tyrosine kinase activity 6, 7. Human epidermal growth factor receptor HER3 (ErbB3) is a cell membrane-associated protein encoded by the ERBB3 gene. This receptor is known as a therapeutic factor in cancer treatment. In addition to HER2 and HER3, both receptors belong to a family of epidermal growth factor receptors (EGFR, HER) tyrosine kinase, and after the dimerization of the receptor, it is activated, which plays an effective role in regulating the cellular signaling pathway 8, 9. Studies have shown that HER3 has a favorable interaction with its structural homologue. Heterodimerization between HER2 and HER3 causes the subsequent signaling cascades of PI3K/AKT and Ras/Raf/MAPK, thus the existence of HER3 as an allosteric activator is required to maintain HER2-mediated signaling, and aberrant HER2-HER3 signaling is strongly associated with carcinogenesis and tumor cell proliferation 10, 11, 12. Studies have shown that overexpression of HER3 protein is significantly effective in the pathogenesis of tumors, which can have adverse clinical consequences. Few studies have been done on the expression of HER3 in pancreatic cancer, which has shown this factor as a prognostic factor. Therefore, the purpose of this study is to investigate the immunohistochemical expression in pancreatic cancer samples and to investigate the relationship between the expression and the clinical pathology of pancreatic cancer patients.

To investigate, tumor samples were collected from pancreatic cancer patients undergoing treatment, and clinical and histopathological characteristics such as age, gender, stage, and grading were evaluated and analyzed. Data were collected from electronic record review, and all study procedures were conducted in accordance with the Declaration on Human Research. This study was conducted on tumor samples collected from patients with pancreatic cancer and undergoing treatment in Ali Ibn Abi Talib Hospital, Zahedan city. Inclusion criteria was Age⩾18 years, having measurable waste ≥2 cm with CT or MRI. The function of the organs is normal and there is no history of chemotherapy and Exclusion criteria was having peripheral neuropathy, brain metastasis, pregnancy, infection, alcohol or drug addiction. The study was approved as a research project in the Faculty of Medicine of Azad University of Zahedan and has a code of ethics. Patients' information such as age, gender, and place of residence were extracted from their medical records. Diagnostic samples were confirmed by the pathologist, and samples with incomplete information in the file, insufficient tissue for examination, or having necrosis and inflammation were excluded from the study.

The present study was performed to evaluate HER3 expression in Pancreatic cancer. The results obtained based on the total score indicated the positive HER3 expression in 19.7% of PC samples. HER3 is one of the four members of epidermal growth factor receptors as ERBB, which is activated by connecting to Neuregulin-1 and Neuregulin-2 ligands. Since HER3 lacks intrinsic kinase activity, induction of signal occurs through formation of Heterodimers with EGFR, HER2 and HER4 13. Most studies examining the HER3 expression in PC 14, 15, in which some significant results were obtained with respect to increased expression and lymph node metastases, prognosis and invasion 16, 17. It was recently found that HER3 plays an important role in response to radiotherapy of head and neck carcinomas and blocking its activity along with radiotherapy may be beneficial for the treatment of human tumors 18. Scharpenseel H et al. 19 studied the expression of HER3 in pancreatic cancer and showed that expression was observed in all samples, and the staining intensity of tumor cells was more intense in invasive areas. The results of another study showed that systemic conditions such as some diseases have an effect on HER3 expression and can indicate cell proliferation and inhibition of apoptosis 20. In a study by Krop I et al. 21 EGFR expression was positive in 60% of pc samples. In a study conducted by Yu HA et al., the intensity of expression HER3 as the first membrane family of receptor tyrosine kinase was related to tumor growth of pancreatic cells 22. Considering that studies have shown that EGFR expression is related to inflammation, therefore, inflammation was identified as a factor to reduce the expression of this receptor in pancreatic cancer. Our study results showed HER-3 expression in 19.7% of tumors. In line with the results of our study Seshacharyulu P et al. showed a significant increase in HER-3 expression in pancreatic cancer compared to control tissue 23. In the present study, the results showed a significant decrease in HER-3 expression and the advanced stage of pancreatic cancer, which is a new result. In line with our study, the results of the study by Capone E et al. showed very low expression of HER-3 in advanced stage ovarian cancer, suggesting that loss of HER-3 expression may be associated with pancreatic tumor stage progression 24. In the investigation conducted by Yonesaka K et al. expression of EGFR was significantly higher in pc samples 25. These results were in contrast with the results of our study. Also, studies showed that the staining factor based on intensity is not a suitable criterion, because the intensity of staining may be reported differently by different pathologists. Also, studies have shown that the high expression of the factor has a direct relationship with causes such as intrinsic growth potential, ability to multiply independently of stimulation, aggressive growth, and high tumor recurrence. It seems that the lack of more studies in the field of expression has led to less knowledge of pancreatic cancer and the causes and identification of its precursors.

Pancreatic cancer is one of the cancers that has a poor prognosis, and more studies are needed for its treatment. This study showed that HER3 highly expressed in the normal tissue of the pancreas, while the expression is lost in the tumor tissue, even the expression decreases from the initial to the final stage. Therefore, it seems that the clinical use of HER-targeted therapy in pancreatic cancer and HER expression is not supported.