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Increased NOS2 predicts poor survival in estrogen receptor–negative breast cancer patients
Sharon A. Glynn, … , Robert M. Stephens, Stefan Ambs
Sharon A. Glynn, … , Robert M. Stephens, Stefan Ambs
Published October 18, 2010
Citation Information: J Clin Invest. 2010;120(11):3843-3854. https://doi.org/10.1172/JCI42059.
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Research Article Oncology

Increased NOS2 predicts poor survival in estrogen receptor–negative breast cancer patients

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Abstract

Inducible nitric oxide synthase (NOS2) is involved in wound healing, angiogenesis, and carcinogenesis. NOS2 upregulation and increased nitric oxide (NO) production affect the redox state of cells and can induce protein, lipid, and DNA modifications. To investigate whether NOS2 levels influence survival of breast cancer patients, we examined NOS2 expression and its association with tumor markers and survival in 248 breast tumors. In multivariable survival analysis, increased NOS2 predicted inferior survival in women with estrogen receptor α–negative (ER-negative) tumors. Microdissected tumor epithelium from ER-negative tumors with high NOS2 had increased IL-8 and a gene expression signature characteristic of basal-like breast cancer with poor prognosis. In cell culture, NO only induced selected signature genes in ER-negative breast cancer cells. ER transgene expression in ER-negative cells inhibited NO-induced upregulation of the stem cell marker CD44 and other proteins encoded by signature genes, but not of IL-8. Exposure to NO also enhanced cell motility and invasion of ER-negative cells. Last, pathway analysis linked the tumor NOS2 gene signature to c-Myc activation. Thus, NOS2 is associated with a basal-like transcription pattern and poor survival of ER-negative patients.

Authors

Sharon A. Glynn, Brenda J. Boersma, Tiffany H. Dorsey, Ming Yi, Harris G. Yfantis, Lisa A. Ridnour, Damali N. Martin, Christopher H. Switzer, Robert S. Hudson, David A. Wink, Dong H. Lee, Robert M. Stephens, Stefan Ambs

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Figure 1

NOS2 expression in human breast tumors.

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NOS2 expression in human breast tumors.
IHC analysis of invasive breast ...
IHC analysis of invasive breast carcinomas for expression of inducible NOS2 (A–D). NOS2 was mainly expressed in the cytoplasm of tumor cells, with some cells showing a marked perinuclear localization of NOS2 protein. NOS2 expression ranged from (A) absent or occasional expression in the tumor epithelium, to (B) moderate expression in numerous tumor cells, to (C and D) a rather strong expression in the tumor epithelium that was either found localized within the tumor or present in most tumor cells. (D) Shown is a tumor with NOS2 expression in both the tumor epithelium and a lymphoid infiltrate (T, tumor epithelium; S, surrounding lymphoid infiltrate). Original magnification, B: ×100, ×200 (inset); A, C, and D: ×200. Counterstain: hematoxylin.

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