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  • br Introduction Breast cancer is the most common malignant t

    2020-01-08


    Introduction Breast cancer is the most common malignant tumor in women and the second leading cause of female death [1]. In recent years, with the improvement of early detection and the emergence of new treatment methods, the mortality rate of breast cancer has been greatly reduced. However, the recurrence rate of distal metastasis of breast cancer is still as high as 20%. After treatment, metastasis and recurrence are the main causes of breast cancer [2]. The molecular mechanism of cell metastasis is particularly important for the prevention and treatment of breast cancer metastasis. In tumor microenvironment, tumor 5-Carboxymethylester-UTP fall off from the solid tumor, enters the blood or the lymphatic circulation, becomes the circulating tumor cells (CTCs) to achieve distant metastasis [3]. During the process, fluid shear stress which is the key participator in mechanical tumor microenvironment plays an essential role in this malignancy. Fluid shear stress in tumor microenvironment mainly includes interstitial fluid, blood and lymph, resulting shear stress. With the occurrence and development of tumors, new blood vessels will be generated in tumors, and the number of lymphatic vessels around tumors will increase significantly. These changes increase the flow of interstitial fluid in tumors. As a result, cancer cells in tumors may be subjected to greater fluid shear stress caused by interstitial fluids. Studies have shown that the shear stress of stromal fluid may promote the metastasis of tumors and form metastatic foci [4]. The shear stress caused by interstitial fluid can promote the migration of breast cancer cells through CCR7 and CCL21 dependent manner [5]. Meanwhile, the shear stress of interstitial fluid can also produce shear stress on the surface of cells, which leads to the stretching of integrins, activation of integrins, activation of intracellular signaling pathways to promote the migration of cancer cells [6]. ERK1/2 signal is a pathway that receives information from the cell membrane and further transmits information to the nucleus, triggering gene transcription and protein expression. The activation of ERK1/2 is mainly achieved by the phosphorylation of Ras and tyrosine. Normally, the connection of stimulants to these receptors stores GTP and activates small molecules GTPase Ras and recruits Raf. Raf phosphorylated MEK1/2 and then ERK1/2 [7]. ERK1/2 is a kinase that can be affected by many factors. Activating ERK1/2 signal can affect a series of functions of cells, such as proliferation, survival, apoptosis and differentiation. Liang et al. reported that low dose ionizing radiation can promote the proliferation of mesenchymal stem cells by activating ERK1/2 signal [8]. In addition to physical stimuli, chemical stimuli can also be converted into cellular signals that affect the cellular response, such as fibroblast growth factor 2 (FGF-2) and fibroblast growth factor 4 (FGF-4) [9,10]. These studies suggested that ERK1/2 is closely related to the proliferation. This study examined whether low shear stress affected the proliferation of breast cancer cells and whether ERK1/2 was involved in the proliferation. YAP (Yes-associated Protein) and TAZ (PDZ-binding motif, also known as WWTR1) transcriptional co-activators have transcriptional co-activation activity, but cannot directly bind DNA, but through interaction with transcription factors such as TEAD, bind themselves to enhancer elements [[11], [12], [13]], regulate the transcriptional process of target genes. Chun-Han Lin and others found that the stiffness of the microenvironment could regulate cell resistance to lapatinib through YAP/TAZ [14]. Meanwhile, YAP, as a mechanoreceptor molecule in cells, can respond to various changes in extracellular mechanical state [15]. For example, when cells have very large spreading area, hard and non-stretchable base of extracellular matrix, cells are in stretching state and are subjected to fluid shear stress, the activation state of YAP will be changed. YAP, as a transcription activator, can regulate the behavior of many kinds of cells, such as cell proliferation, migration, invasion, metastasis, EMT, chemotherapy resistance [[16], [17], [18]] and self-renewal of cancer stem cells.