Trastuzumab, an epidermal growth factor receptor 2 (HER2) targeting humanized monoclonal antibody, has been approved for the treatment HER2-positive breast cancer and HER2-positve metastatic gastric cancer. However, cardiotoxicity associated with its clinical application poses challenges clinicians patients, mechanisms of which are still evolving. This review will summarize current mechanistic understanding trastuzumab-mediated cardiotoxicity, discuss novel role DNA topoisomerase IIB as a...

Treatment with trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of Human Epidermal Growth Factor Receptor 2 (HER2), very successfully improves outcomes for women HER2-positive breast cancer. However, trastuzumab treatment was recently linked to potentially irreversible serious cardiotoxicity, mechanisms which are largely elusive. This study reports that significantly alters expression myocardial genes essential DNA repair, cardiac and mitochondrial...

Abstract Dysregulation of autophagy has been implicated in various cardiovascular diseases. Trastuzumab, a humanized monoclonal antibody, binds to HER2 domain IV and is approved for the treatment HER2-positive breast cancer. Trastuzumab therapy associated with considerable cardiotoxicity, mechanism which remains unclear. signaling plays pivotal role cardiomyocyte development survival essential prevention cardiomyopathy. However, direct link not confirmed between trastuzumab-induced...

E-cadherins play an essential role in maintaining epithelial polarity by forming Ca2+-dependent adherens junctions between cells. Here, we report that Ca2+ depletion induces E-cadherin ubiquitination and lysosomal degradation Cdc42 plays important regulating this process. We demonstrate activation of Cdc42. This turn up-regulates epidermal growth factor receptor (EGFR) signaling to mediate Src activation, leading degradation. Silencing blocks EGFR induced depletion, resulting a reduction The...

Abstract Although treatment with trastuzumab improves outcomes for women ErbB2-positive breast cancer, many patients who achieve an initial response to subsequently acquire resistance within 1 year. Rac1, a Ras-like small GTPase, has been implicated in the control of cell growth and morphology is believed be associated cancer progression metastasis. Here, we show that when parental SKBR3 cells become resistant trastuzumab, Rac1 activity increased, leading altered morphology, which...

Treatment of cells with epidermal growth factor (EGF) promotes the activation small GTP-binding protein Cdc42, as well its phosphorylation in cells. The EGF-dependent Cdc42 occurs at tyrosine 64 Switch II domain and appears to be mediated through Src kinase, because both expression a dominant-negative mutant (mouse Src(K297R)) treatment kinase inhibitor PP2 blocks EGF-stimulated whereas an activated (Src(Y529F)) absence EGF treatment. is not required for activation, nor does it directly...

Overexpression of epidermal growth factor receptor (EGFR) contributes to increased cell proliferation and migration in breast cancer. However, mechanisms EGFR overexpression remain elusive often cannot be attributed gene amplification. In NIH3T3 fibroblasts, active Cdc42 inhibits c-Cbl-regulated degradation induce cellular transformation. Here, we use two EGFR-overexpressing cancer lines, MDA-MB-231 BT20, as models test the hypothesis that up-regulated activity impairs c-Cbl-mediated...

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive metastatic breast cancer. It consists trastuzumab, a humanized mAb directed against HER2, and microtubule inhibitor, DM1, conjugated to trastuzumab via thioether linker. Hepatotoxicity one serious adverse events associated with T-DM1 therapy. Mechanisms underlying T-DM1-induced hepatotoxicity remain elusive. Here, we use hepatocytes mouse models investigate mechanisms...

The inhibitory effect of trastuzumab, a humanized monoclonal antibody directed against the extracellular domain ErbB2, is associated with its ability to induce ErbB2-Y1248 phosphorylation, and status phosphorylated (ErbB2-pY1248) may correlate sensitivity breast cancers trastuzumab. mechanisms which remain unclear. Here, we show that binding trastuzumab ErbB2 activates kinase activity enhances phosphorylation in trastuzumab-sensitive cancer cells. This turn increases interaction between...

Immune check point inhibitors targeting programmed cell death protein-1 (PD-1) and its ligand (PD-L1) have shown clinical success in treatment of human malignancies. Triple negative breast cancer (TNBC), which is primarily characterized by high heterogeneity presence tumor infiltrating lymphocytes, remains therapeutic challenge due to unavailability approved targeted therapy. Therapeutic potential immune for TNBC patients under active investigation. In this study, we show that FDA-approved...

Members of the Rho subfamily Ras-related GTP-binding proteins play important roles in organization actin cytoskeleton and regulation cell growth. We have shown previously that <i>dbl</i> oncogene product, which represents a prototype for family growth regulatory proteins, activates by catalyzing dissociation GDP from their nucleotide binding site. In present study, we demonstrate acidic phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP₂), provides an alternative mechanism...

Cdc42 is a low molecular weight GTP-binding protein that plays key regulatory role in variety of cellular activities. The importance the coordination different cell functions by underscored fact constitutively active mutant induces transformation. In this study, we describe novel function for Cdc42: its ability to stimulate pre-messenger RNA splicing. This activity dependent on cysteine 37 effector loop but not growth. A likely candidate mediating effects pre-mRNA splicing nuclear...

Conventional spherical simplex-radial cubature Kalman filter (SSRCKF) for maneuvering target tracking may decline in accuracy and even diverge when a makes abrupt state changes. To overcome this problem, novel algorithm named strong (STSSRCKF) is proposed paper. The uses the (SSR) rule to obtain higher than (CKF) algorithm. Meanwhile, by introducing (STF) into SSRCKF modifying predicted states’ error covariance with time-varying fading factor, gain matrix adjusted on line so that robustness...

Both EGFR and VEGFR2 frequently overexpress in TNBC cooperate with each other autocrine paracrine manner to enhance tumor growth angiogenesis. Therapeutic mAbs targeting (cetuximab) (ramucirumab) are approved by FDA for numerous cancer indications, but none of them treat breast cancers. cells secrete VEGF-A, which mediates angiogenesis on endothelial a fashion, as well promotes cell manner. To disrupt autocrine/paracrine loop models addition mediating anti-EGFR signaling anti-VEGFR2...

Cdc42, a Ras-related GTP-binding protein, has been implicated in the regulation of actin cytoskeleton, membrane trafficking, cell-cycle progression, and malignant transformation. We have shown previously that Cdc42 mutant (Cdc42(F28L)), capable spontaneously exchanging GDP for GTP (referred to as "fast-cycling"), transformed NIH 3T3 cells because its ability interfere with epidermal growth factor receptor (EGFR)-Cbl interactions EGFR down-regulation. To further examine link between...

Despite heightened risk of cardiotoxicity associated with combination therapy anthracyclines and trastuzumab in HER2-positive breast cancer patients, little research effort has been invested exploring the molecular mechanisms induced by this therapy. In study, we demonstrate that downregulates both gene protein expressions type IIB DNA topoisomerase/DNA topoisomerase (TOP2B), a major intracellular target mediating doxorubicin-induced cardiotoxicity, human primary cardiomyocytes. This turn...

// Nishant Mohan 1 , Yi Shen Milos Dokmanovic Yukinori Endo Dianne S. Hirsch Wen Jin Wu Division of Biotechnology Review and Research I, Office Products, Pharmaceutical Quality, Center for Drug Evaluation Research, U.S. Food Administration, Silver Spring, 20993, Maryland, USA Correspondence to: Wu, email: Wen.Wu@fda.hhs.gov Keywords: VPS34, TSC1/TSC2, RheB, mTORC1/S6K1, cellular transformation Received: January 22, 2016 Accepted: June 07, Published: July ABSTRACT VPS34 is reported to...