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26-10-2010 | Oncology | Article

NOS2 potential therapy target for ER-negative breast cancers

Abstract

Free abstract

MedWire News: High expression of inducible nitric oxide synthase (NOS)2 is associated with an aggressive tumor phenotype and poor survival among women with estrogen receptor α (ER)-negative breast cancer, US research shows

"This suggests that NOS2 is a novel candidate prognostic marker… and possibly a therapeutic target, whose activity could be selectively inhibited," remark Stefan Ambs (National Cancer Institute, Bethesda, Maryland) and colleagues.

They explain that NOS2 is an enzyme involved in wound healing, angiogenesis, and carcinogenesis. Upregulation of the enzyme leads to increased NO production, which affects the redox state of cells, they add.

To investigate whether NOS2 levels influence breast cancer survival, Ambs and team examined expression of the protein in tumors from 248 women with breast cancer.

Tumors that had an immunohistochemistry staining intensity score of 0-1 were classed as having low NOS2 expression, while those with a score of 2-3 had high expression.

The researchers report that, compared with low NOS2 expression, high expression was independently associated with mutation in the p53 tumor suppressor gene (odds ratio [OR]=3.02), higher tumor grade (grade 3 vs grade 1/2; OR=2.86), and greater microvessel density (above vs below median; OR=2.41).

Furthermore, high NOS2 expression was significantly associated with decreased survival in ER-negative patients, but not in ER-positive patients.

To determine the reason for this, the team analyzed the gene expression profiles in the epithelium of 32 tumors. They found that ER-negative tumors with high NOS2 expression had a gene expression signature characteristic of aggressive basal-like breast cancer as well as increased interleukin (IL)-8 expression.

The researchers suggest that selective induction of IL-8 among ER-negative patients may lead to poor survival via increased stem cell renewal, cell invasion, angiogenesis, and metastasis.

Induction of a basal-like phenotype, activation of the epidermal growth factor receptor pathway, and selection for mutant p53 cells may also be involved in an nitric oxide-induced poor outcome phenotype, they add.

"There is an urgent need to identify novel targets for the treatment of ER-negative breast cancer in general, and even more for the aggressive basal-like subtype, which has limited therapy options," write Ambs and co-authors in the Journal of Clinical Investigation.

"We propose that selective NOS2 inhibitors may be particularly efficacious in [these] patients," they conclude.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

By Laura Dean

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