RT Journal Article
T1 Altered S-nitrosothiol homeostasis provides a survival advantage to breast cancer cells in HER2 tumors and reduces their sensitivity to trastuzumab.
A1 Cañas, Amanda
A1 López-Sánchez, Laura M
A1 Peñarando, Jon
A1 Valverde, Araceli
A1 Conde, Francisco
A1 Hernández, Vanessa
A1 Fuentes, Elena
A1 López-Pedrera, Chary
A1 de la Haba-Rodríguez, Juan R
A1 Aranda, Enrique
A1 Rodríguez-Ariza, Antonio
K1 Apoptosis
K1 Breast cancer
K1 HER2/neu
K1 Nitric oxide
K1 S-nitrosoglutathione reductase
K1 S-nitrosylation
AB 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.
SN 0006-3002
YR 2016
FD 2016-02-06
LK https://hdl.handle.net/10668/28262
UL https://hdl.handle.net/10668/28262
LA en
DS RISalud
RD Apr 4, 2025