title: Altered S-nitrosothiol homeostasis provides a survival advantage to breast cancer cells in HER2 tumors and reduces their sensitivity to trastuzumab.
abstract: The monoclonal antibody trastuzumab against HER2/neu, which is overexpressed in 15-20% of breast cancers, has clinical efficacy but many patients do not respond to initial treatment or develop resistance during treatment. Nitric oxide (NO) regulates cell signaling by targeting specific cysteine residues in proteins, forming S-nitrosothiols (SNO) in a process known as S-nitrosylation. We previously reported that molecular characteristics in breast cancer may dictate the tumor response to impaired SNO homeostasis. In the present study, we explored the role of SNO homeostasis in HER2 breast tumors. The antiproliferative action of trastuzumab in HER2-overexpressing BT-474 and SKBR-3 cells was suppressed when S-nitrosoglutathione reductase (GSNOR/ADH5) activity, which plays a key role in SNO homeostasis, was specifically inhibited with the pyrrole derivative compound N6022. Moreover, GSNOR inhibition restored the activation of survival signaling pathways involved in the resistance to anti-HER2 therapies (AKT, Src and c-Abl kinases and TrkA/NRTK1, TrkB/NRTK2, EphA1 and EphA3 receptors) and reduced the apoptotic effect of trastuzumab. Accordingly, GSNOR inhibition augmented the S-nitrosylation of apoptosis-related proteins, including Apaf-1, pSer73/63 c-Jun, calcineurin subunit α and HSF1. In agreement with in vitro data, immunohistochemical analyses of 51 breast tumors showed that HER2 expression was associated with lower expression of GSNOR protein. Moreover, gene expression analysis confirmed that high ADH5/GSNOR gene expression was associated with high patient survival rates in HER2 tumors. In conclusion, our data provide evidence of molecular mechanisms contributing to the progression of HER2+ breast cancers and could facilitate the development of therapeutic options to counteract resistance to anti-HER2 therapies.
authors: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: amandacanasrodriguez@gmail.com.
authors: Amanda
authors: A
authors: Cañas
authors: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: lmlopezsanchez@gmail.com.
authors: Laura M
authors: LM
authors: López-Sánchez
authors: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: jon_aries80@hotmail.com.
authors: Jon
authors: J
authors: Peñarando
authors: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: aracelivalverdeestepa@hotmail.es.
authors: Araceli
authors: A
authors: Valverde
authors: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: fmcp@usal.es.
authors: Francisco
authors: F
authors: Conde
authors: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: vanessa-septiembre@hotmail.com.
authors: Vanessa
authors: V
authors: Hernández
authors: Pathology Department, IMIBIC, Reina Sofía Hospital, University of Córdoba, Spain. Electronic address: elena.fuentes.sspa@juntadeandalucia.es.
authors: Elena
authors: E
authors: Fuentes
authors: Research Unit, IMIBIC, Reina Sofía Hospital, University of Córdoba, Córdoba, Spain. Electronic address: rosario.lopez.exts@juntadeandalucia.es.
authors: Chary
authors: C
authors: López-Pedrera
authors: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: juahaba@gmail.com.
authors: Juan R
authors: JR
authors: de la Haba-Rodríguez
authors: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: earandaa@seom.org.
authors: Enrique
authors: E
authors: Aranda
authors: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: antonio.rodriguez.exts@juntadeandalucia.es.
authors: Antonio
authors: A
authors: Rodríguez-Ariza
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D061986:MCF-7 Cells; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D026403:S-Nitrosothiols / Q000378:metabolism*; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D026403:S-Nitrosothiols; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: Apoptosis; Breast cancer; HER2/neu; Nitric oxide; S-nitrosoglutathione reductase; S-nitrosylation