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Figure 1. Mechanisms of growth hormone mediated therapy resistance in human cancers: (A) therapeutic interventions (radiation or chemotherapy) which cause DNA damage in tumor cells (1), induce ATM (2) mediated p53 production (3) which directly increases GH production (4). This GH can have an autocrine/paracrine effect on binding to same or neighboring cell surface GH receptors (GHR) (5), initiating a JAK2 and SRC mediated signaling cascades which lead to elevated TRIM29 and decreased Tip60(6), which in turn blocks ATM (7) and decreases p53 via feedback inhibition. GH-GHR interaction also decreases pro-apoptotic molecules (Bax, PPARγ) and suppresses Caspase activation (8) thus allowing escape from cell death and providing resistance to therapy; (B) GH-GHR interaction drives resistance against pharmacologic intervention (chemotherapy or targeted therapy) by upregulating ABC-multidrug efflux pumps, inducing epithelial-to-mesenchymal transition or EMT (elevated mesenchymal transcription factors SNAI1, SNAI2, ZEB1/2, TWIST1/2, CLDN1, VIM, and miRNA cluster 96-182-183, along with decreased CDH1, and increased CDH2) and by inducing markers of stemness like ALDH1, NANOG, and CD24 to effect a phenotype switch. The combination of GH mediated suppression of apoptosis, increased capacity of drug efflux, increased stemness and invasive mesenchymal properties allow therapy resistance, metastasis, and relapse of the tumor. Green arrow indicates upregulation while red arrow indicates downregulation of target gene expression