Breast cancer is the most prevalent metastatic tumor and the main cause of cancer-related death among women all over the world, where its curability remains a challenging task till now [
1]. Long-term exposure to high level of steroidal hormones plays an integral role in the incidence of breast cancer, whereas the role of non-steroidal hormone was inadequately investigated. AVP, for example, is constitutively synthesized in the hypothalamus and functions mainly on kidney’s collecting duct cells. The signaling effect of AVP is mediated by G-protein coupled receptors (GPCRs) including vasopressin type 1 receptors (V1aR, V1bR also called V3R) and vasopressin type 2 receptor (V2R) [
2,
3]. AVP and its receptors, however, are ectopically expressed in several cancers, including breast cancer. Breast cancer cell lines, like MCF-7, Skbr3, BT474, ZR75 and Mcf10a, in addition to human breast cancer tissues, were found to abnormally express AVP [
4]. Moreover, earlier studies showed that MCF-7 cells express mRNAs of all isoforms of the AVP receptors [
5]. This makes breast cancer cells responsive to AVP as an autocrine growth factor. Beyond its classical functions in regulating water and solute transport in renal cells, AVP/V2R downstream signaling may involve a range of other cellular functions [
6]. Expression of AVP in some cancers leads to the production of both normal and abnormal forms of tumor AVP mRNA and proteins [
7] and triggers the growth of cell lines like breast, small cell lung cancer [
8,
9], and mamary tumor growth in vivo [
10]. In contrast, some investigations showed that AVP had no stimulatory effect on growth of small cell lung cancer or adreno-cortical tumor [
11]. Other reports demonstrated that AVP has dose-dependent contradicting effects [
12]. Regardless the receptor isoform it binds with, AVP may undergo clathrin-mediated endocytosis (CME) that involves several cellular endocytic proteins including Dynamin 2 (Dyn2), a member of large-guanosine 5’-triphosphatase (GTPase) family. Structurally, Dyn2 is multimodular protein composed of five conserved domains, including the large N-terminal GTPase domain (also, called G-domain) [
13,
14]. In CME, soluble Dyn2 monomers are recruited to the neck of the nascent liganded receptor-containing clathrin coated vesicles (CCVs) forming a helical oligomer that catalyzes CCVs fission from plasma membrane [
15,
51]. In 2006, 3-hydroxynaphthalene-2-carboxylic acid-(3,4-dihydroxybenzylidene)-hydrazide (commonly known as Dynasore, DYN) was introduced as the first large dynamin GTPase inhibitor, where it selectively inhibits Dyn isoforms, (Dyn1, Dyn2 and Dyn3 GTPases), without affecting small GTPases [
16]. Compared to RNAi-mediated inhibition of genes encoding Dyn2, Dynasore also, reduces labile cholesterol in the plasma membrane and disrupts lipid raft organization in a dynamin-independent manner [
17], that may enhance its role as an endocytic inhibitor. The direct involvement of Dyn2 in cancer development (reviewed by [
21]), nominated him as a promising anticancer target. In the same context, some reports revealed that invasive cancer cells requires Dyn2 for the internalization of several proteins involved in cancer cell motility and invasiveness by the endocytosis process [
18]. Other studies have reported that Dyn2 may act as a facilitator of focal adhesion turnover during cell migration and invasion [
19], and vascular endothelial growth factor (VEGF)-mediated angiogenesis [
20,
21]. Collectively, these observations suggest the key role of Dyn2 in the progression of luminal A breast cancer towards invasiveness and metastasis. In this regard, the combined effect of AVP stimulation and Dyn2 inhibition was not adequately exploded. Moreover, it is not clear how the DYN-mediated inhibition of Dyn2 will modulate AVP-stimulated breast cancer cells proliferation, and migration. Thus, this work is designed to explore the anti-proliferative and antimetastasis effects of Dynasore in a luminal A breast cancer cells, which was prestimulated with exogenous AVP. Also, the associated involvement of phosphatidylinositol 3-kinase (PI3K) pathway will be investigated.