The Breast Cancer Protooncogenes HER2, BRCA1 and BRCA2 and Their Regulation by the iNOS/NOS2 Axis

Abstract

The expression of inducible nitric oxide synthase (iNOS; NOS2) and derived NO in various cancers was reported to exert pro- and anti-tumorigenic effects depending on the levels of expression and the tumor types. In humans, the breast cancer level of iNOS was reported to be overexpressed, to exhibit pro-tumorigenic activities, and to be of prognostic significance. Likewise, the expression of the oncogenes HER2, BRCA1, and BRCA2 has been associated with malignancy. The interrelationship between the expression of these protooncogenes and oncogenes and the expression of iNOS is not clear. We have hypothesized that there exist cross-talk signaling pathways between the breast cancer protooncogenes, the iNOS axis, and iNOS-mediated NO mutations of these protooncogenes into oncogenes. We review the molecular regulation of the expression of the protooncogenes in breast cancer and their interrelationships with iNOS expression and activities. In addition, we discuss the roles of iNOS, HER2, BRCA1/2, and NO metabolism in the pathophysiology of cancer stem cells. Bioinformatic analyses have been performed and have found suggested molecular alterations responsible for breast cancer aggressiveness. These include the association of BRCA1/2 mutations and HER2 amplifications with the dysregulation of the NOS pathway. We propose that future studies should be undertaken to investigate the regulatory mechanisms underlying the expression of iNOS and various breast cancer oncogenes, with the aim of identifying new therapeutic targets for the treatment of breast cancers that are refractory to current treatments.

IL-21/IL-21R Promotes the Pro-Inflammatory Effects of Macrophages during C. muridarum Respiratory Infection

“…Nitric oxide (NO), an M1-activation marker, is a crucial pro-inflammatory mediator in the pathogenesis of several inflammatory disease [ 33 , 34 ]. The release of NO is tightly regulated by the iNOS level, whose expression depends on reactive oxygen species (ROS) accumulation [ 34 , 35 ]. ARG1, involved in the conversion of L-arginine to L-ornithine and polyamines, is reported to be an important marker of M2 function [ 22 ].…”

The Nitric Oxide Donor [Zn(PipNONO)Cl] Exhibits Antitumor Activity through Inhibition of Epithelial and Endothelial Mesenchymal Transitions

“…While we demonstrated an anti-inflammatory effect (see the inhibition of TGF-β1 signaling and the physiological protective effect of NO in the cardiovascular system), NO has been demonstrated to play a crucial role in the development of chronic inflammation. As example, the presence of NO in cancer may regulate tumor-associated macrophage metabolism and function, favoring the persistence of inflammation in tumorigenesis and cancer stemness [ 63 , 64 , 65 , 66 , 67 ]. These findings appear tissue-specific, since in most of the reports the association high NO levels with inflammation, oxidative status, DNA damage and tumorigenesis has been described for cancer of the gastrointestinal apparatus, upper airways, the reproductive organs and the breast.…”

Phytochemical characterization by GC-MS and in vitro evaluation of antiproliferative and antimigratory studies of Leucas aspera leaf extracts on MDA-MB-231 cell line

“…In breast cancer cells this BRCA1 gene is mutated therefore it cannot repress the estrogen receptor α (ER-α) resulting in the development of TNBC (Sengodan et al, 2018 ). This mutation indirectly promotes the carcinogenesis of other genes by increasing their mutation rate (Lin et al, 2022 ).…”