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Contribution of nitric oxide synthase dysfunction and its cofactor tetrahydrobiopterin in positive and negative estrogen receptor breast carcinomas development

Grant number: 16/14536-8
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): October 01, 2017
Effective date (End): September 30, 2018
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Fabiana Henriques Machado de Melo
Grantee:Andrei Ronaldo Oliveira Silva Escartin Salas
Home Institution: Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP). Fundação Arnaldo Vieira de Carvalho. São Paulo , SP, Brazil

Abstract

Breast cancer is a heterogeneous disease that is presented in many different ways, receptors and biochemical pathways of many types of breast tissue cell are affected, resulting in a different cell behavior, that allows the cell survive in situations that would damage a normal cell. Many types of breast cancer have been described, including those related to changes in the expression and activity of nitric oxide synthase (NOS), that may be producing high levels of nitric oxide (NO), or may be uncoupled, and in this last case it would produce superoxide anion (O2-). NOS gets uncoupled because its cofactor BH4 is in low levels and BH2, the partially oxidized form of BH4, is overproduced, and BH2 competes for the same binding site of BH4 in NOS. Tumor cells can survive in a pro-oxidant environment, which would not be possible for a normal cell, so it is possible that the NOS uncoupling is related to the development and activity of the tumor. Mammary carcinomas may or may not have estrogen receptor (ER+ or ER-), and in most of the cases the ER+ breast cancer would be treated more easily because the interference with the receptor activator hormone or with the receptor itself makes cell survival more difficult by preventing the activation of signal transduction pathways that activates proliferation mechanisms, such as increased production of superoxide anion. However, not all ER+ breast cancers respond to these treatments, and some ER- breast cancer can respond to these treatments, indicating that the mechanisms of proliferation and survival of breast cancer are not completely understood, meaning that there are other ways to activate pathways that increase the production of reactive oxygen species (ROS), for example the dysfunction of NOS.