Abstract:Acquired tamoxifen-resistance is an important cause of death in patients with hormone-dependent breast tumors. Therefore, understanding the molecular mechanisms underlying the development of tamoxifen-resistance is critical for successful endocrine therapy. This study aimed to define the role of WW domain-containing oxidoreductase (WWOX) in acquired tamoxifen-resistance. Our results show that low WWOX expression was significantly related to tamoxifen-resistance. Moreover, WWOX-knockdown increased resistance to… Show more
“…Supporting research from WWOX also shows this protein may oversee the Hippo signaling pathway from the upstream via interacting with proteins in the TGF-β, hyaluronidase Hyal-2, and Wnt/β-catenin pathways (Chen et al). In supporting this notion, a recent study reported that downregulation of WWOX results in tamoxifen resistance in breast cancer due to inactivation of Hippo signaling (3). Lee and Liou described the structure and the functional nature of Pin1.…”
“…Supporting research from WWOX also shows this protein may oversee the Hippo signaling pathway from the upstream via interacting with proteins in the TGF-β, hyaluronidase Hyal-2, and Wnt/β-catenin pathways (Chen et al). In supporting this notion, a recent study reported that downregulation of WWOX results in tamoxifen resistance in breast cancer due to inactivation of Hippo signaling (3). Lee and Liou described the structure and the functional nature of Pin1.…”
“…Simultaneous inhibition of YAP1 and ROR1 in combination with conventional HER‐2 therapy may overcome treatment resistance problem 203 . Evidence suggests that WW domain‐containing oxidoreductase inhibits YAP activity by increasing the phosphorylation of YAP in breast cance 204 . The antipsychotic drug chlorpromazine inhibits BC cell stemness, downregulates Hippo–YAP signaling, and increases BC cell resistance to drugs 244 .…”
Section: Hippo Pathway In Cancer Drug Resistancementioning
confidence: 99%
“… 203 Evidence suggests that WW domain‐containing oxidoreductase inhibits YAP activity by increasing the phosphorylation of YAP in breast cance. 204 The antipsychotic drug chlorpromazine inhibits BC cell stemness, downregulates Hippo–YAP signaling, and increases BC cell resistance to drugs. 244 Moreover, methotrexate‐free can make BC stem cell lines and related tumors more sensitive to the drug resistance of transplanted tumors.…”
Section: Hippo Pathway In Cancer Drug Resistancementioning
As highly conserved among diverse species, Hippo signaling pathway regulates various biological processes, including development, cell proliferation, stem cell function, tissue regeneration, homeostasis, and organ size. Studies in the last two decades have provided a good framework for how these fundamental functions of Hippo signaling are tightly regulated by a network with numerous intracellular and extracellular factors. The Hippo signaling pathway, when dysregulated, may lead to a wide variety of diseases, especially cancer. There is growing evidence demonstrating that dysregulated Hippo signaling is closely associated with tumorigenesis, cancer cell invasion, and migration, as well as drug resistance. Therefore, the Hippo pathway is considered an appealing therapeutic target for the treatment of cancer. Promising novel agents targeting the Hippo signaling pathway for cancers have recently emerged. These novel agents have shown antitumor activity in multiple cancer models and demonstrated therapeutic potential for cancer treatment. However, the detailed molecular basis of the Hippo signaling‐driven tumor biology remains undefined. Our review summarizes current advances in understanding the mechanisms by which Hippo signaling drives tumorigenesis and confers drug resistance. We also propose strategies for future preclinical and clinical development to target this pathway.
“…Moreover, Zheng et al [ 108 ] found that the YAP-glycolysis axis was also a target for overcoming tamoxifen resistance, based on the fact that the Hippo pathway was downstream of GPER. Li et al [ 109 ] confirmed that downregulated YAP phosphorylation and upregulated YAP nuclear translocation directly resulted in tamoxifen resistance, which was reversed by YAP silencing. Fig.…”
Section: The Cross Talk Between the Hippo Pathway And Multiple Pathways Involved In Endocrine Resistancementioning
Drug resistance is always a great obstacle in any endocrine therapy of breast cancer. Although the combination of endocrine therapy and targeted therapy has been shown to significantly improve prognosis, refractory endocrine resistance is still common. Dysregulation of the Hippo pathway is often related to the occurrence and the development of many tumors. Targeted therapies of this pathway have played important roles in the study of triple negative breast cancer (TNBC). Targeting the Hippo pathway in combination with chemotherapy or other targeted therapies has been shown to significantly improve specific antitumor effects and reduce cancer antidrug resistance. Further exploration has shown that the Hippo pathway is closely related to endocrine resistance, and it plays a “co-correlation point” role in numerous pathways involving endocrine resistance, including related pathways in breast cancer stem cells (BCSCs). Agents and miRNAs targeting the components of the Hippo pathway are expected to significantly enhance the sensitivity of breast cancer cells to endocrine therapy. This review initially explains the possible mechanism of the Hippo pathway in combating endocrine resistance, and it concludes by recommending endocrine therapy in combination with therapies targeting the Hippo pathway in the study of endocrine-resistant breast cancers.
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