Genetic Polymorphisms of eNOS, Hormone Receptor Status, and Survival of Breast Cancer

Abstract

The endothelial cell-specific form of nitric oxide synthase (eNOS) may play an important role in tumor progression via angiogenesis or apoptosis. We studied eNOS -786T > C and 894G > T (Glu298Asp), two functionally significant SNPs, in relation to hazard of breast cancer recurrence or death in 873 women with incident, non-metastatic breast cancer, recruited from two teaching hospitals in Seoul, Korea, 1995-2002. Hazards were estimated by Cox proportional hazard models, in relation to genotype, adjusting for hormone receptor status, lymph node involvement, and tumor size. Women carriers of the eNOS -786C allele had significantly increased hazards of breast cancer recurrence or death, compared with women having the TT genotype (HR = 2.1, 95% CI = 1.03-4.33); risks increased up to 3-fold in ER positive cases (HR = 3.2, 95% CI = 0.95-10.50). The hazard was also increased in eNOS 894T carriers, however, it did not reach statistical significance (HR = 1.8, 95% CI = 0.85-3.93). The combined genotypes containing -786C or 894T was associated with a 2.5-fold risk, compared to the TT-GG genotypes, the most dominant genotype combination (95% CI = 1.29-4.68), with the greatest risks in ER positive cases (HR = 4.9, 95% CI = 1.31-18.36). These results indicate that the eNOS -786C polymorphism, and possibly the 894T polymorphism, are associated with breast cancer recurrence and death, particularly in women with ER positive tumors.

Expression of angiogenic markers in the peripheral blood of docetaxel-treated advanced breast cancer patients: A Hellenic Cooperative Oncology Group (HeCOG) study

“…Notably, low eNOS immunohistochemical expression has been found to be associated with adverse prognostic features (23) and poor survival (24). Moreover, Choi et al reported poor survival in breast cancer patients bearing polymorphisms associated with low eNOS activity (25,26). Also, as in our study (trend for significance shown in Table III), other investigators (23,27) found higher eNOS mRNA expression in hormone receptorpositive tumors.…”

An Emerging Role for Endothelial Nitric Oxide Synthase in Chronic Inflammation and Cancer

“…Genetic comparison studies on healthy people and cancer victims have shown that gene polymorphisms in eNOS are associated with the development of multiple cancers (15,16). Although the functional effect of eNOS polymorphisms has yet to be determined, these data support the hypothesis that an abnormal eNOS gene might drive tumorigenesis in humans.…”

Genetic predictors of long‐term toxicities after radiation therapy for breast cancer

“…Myeloperoxidase (MPO) and endothelial nitric oxide synthase (eNOS) generate ROS, and polymorphisms resulting in reduced expression of these enzymes have been linked to poorer breast cancer survival. 21,22 Manganese superoxide dismutase (MnSOD), catalase (CAT) and glutathione-S-transferases (GSTs) are involved in pathways that neutralize ROS, and genotypes associated with higher levels of oxidative stress have been associated with better breast cancer survival. 21,23,24 Although higher levels of ROS may result in better tumor cell kill and thus, better survival, genetic variants that result in generation of ROS may also predispose to higher risk of skin toxicities.…”