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

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 4

Induction of IL-8, S100A8, CD44, and P-cadherin in ER-negative breast cancer cell lines after exposure to the NO donor DETA/NO.

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Induction of IL-8, S100A8, CD44, and P-cadherin in ER-negative breast ca...
(A) DETA/NO induced IL-8 secretion in the two ER-negative cell lines MDA-MB-231 and MDA-MB-468, over a 48-hour exposure, but not in the ER-positive cell lines T47D and MCF-7. Shown are mean ± SD. *P < 0.05 versus no treatment, Student’s t test. (B) DETA/NO induced increased protein expression of CD44, P-cadherin, and S100A8 in the ER-negative cell lines MDA-MB-231 and MDA-MB-468 over a 48-hour exposure, with no or opposite effects in the ER-positive cell lines T47D and MCF-7. ELISA was used for IL-8. Pos ctrl, positive control.