الفهرس 
Breast cancer as a major health problemOnly 14 pages are availabe for public view
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Abstract
Breast cancer is the most significant worldwide female-related public health problem, where it is considered the main reason for female mortality around the world. In 2020 there are about 2.3 million cases were diagnosed with breast cancer with approximately 685,000 deaths worldwide (Burstein et al., 2021). Breast cancer is strongly associated with disturbance in both steroidal and nonsteroidal hormones. The implication of steroid hormones and their nuclear receptors including endogenous estrogen, progesterone and their corresponding estrogen receptor (ER), and progesterone receptor (PR) is well reported (Manna et al., 2022). More than 70% of breast cancers are considered hormone receptor-positive (ER+, PR+ and HER2+). The risk incident of breast cancer is strongly related to long-term exposure to high levels of these steroidal hormones. Breast cancer is not only associated with reproductive hormones but also associated with abnormally expression of vasopressin (AVP) and its receptors. Several studies showed that the gene express AVP hormone as a prohormone is observed in many endocrine tumors. Long-term exposure to high levels of steroidal hormones plays an integral role in the incidence of breast cancer, whereas the role of non-steroidal hormones was inadequately investigated. AVP hormone and its receptors is not only normally expressed in normal renal cells (HEK-293), but also expressed ectopically in abnormal tumor cells not responsible for its production originally like breast cancer cells. AVP in the human body is to mediate the volume of fluid by monitoring the renal handling of water so it is called vasoconstrictor. The effect of AVP is largely orchestrated through its downstream signaling and by receptor-mediated endocytosis (RME), in which Dynamin 2 (Dyn2) plays an integral role in vesicle closure. The effect of AVP may be mitogenic effect or anti-proliferative effect on cancer cells depending on dose of AVP or type of receptor. The associated expression of AVP receptors on the cell membrane of breast cancer cells makes it susceptible to the autocrine and the endocrine effects of AVP or its analogs. Therefore, inhibition of endocytic proteins like Dynamin 2 (Dyn2), clathrin, and/or β-arrestins will affect AVP function either through endocytosis or through endocytosis-independent effect. Pathologically, several studies have indicated the participation of Dynamin isoforms (Dyn1&Dyn2) in the tumorigenesis and their enhancing role in tumor invasion and metastasis. Also, abnormally expressed, or mutated Dyns, were reported in many cancers, like colon adenocarcinomas and non-small cell lung cancer (NSCLC). The inhibition of early endocytic events of CME, through inhibiting the interaction between β-arrestin and AP2 adaptor protein induced apoptosis in invasive breast cancer. This work aimed to explore the antiproliferative and the antimetastatic effects of AVP and DYN combination in HER2-negative and HER2-postive breast cancer cells and compare them with the corresponding effect of pan-PI3K inhibitor (Wortmannin), in presence or absence of DYN. To achieve the aim of the work we used 3 cell lines including luminal A breast cancer cells, triple-negative breast cancer cells and HEK-293 cell line. The luminal A breast cancer cells and triple-negative breast cancer cells were treated with 100 nM AVP, and then Dynasore (DYN) was employed to inhibit Dyn2 to explore the combined effect of AVP and Dyn2 inhibition on the survival of breast cancer cells. Furthermore, cell viability assay was performed to define the cytotoxic effect and determine the IC50 values of DYN using different concentrations of DYN and incubated at 37 °C in 5% CO2 for 24 h on both cancer cells. The apoptosis assay followed by autophagy assessments were matched with the corresponding effect of Wortmannin-mediated PI3K/Akt inhibition.