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Mechanisms of nitric oxide synthase-2 (NOS2) induction and downstream signaling in breast cancer

Wednesday, November 06, 2013 — Poster Session I

4:00 p.m. – 6:00 p.m.

FAES Academic Center (Upper-Level Terrace)




  • J.L. Heinecke
  • L.A. Ridnour
  • R.Y. Cheng
  • C.H. Switzer
  • M.M. Lizardo
  • C Khanna
  • S Glynn
  • S.P. Hussain
  • H Young
  • S Ambs
  • D.A. Wink


Breast cancer is the second leading cause of cancer-related deaths among women worldwide. Clinical management is becoming more personalized because of recent advances in our understanding of the tumor biology. However, our knowledge of the complex signaling network in breast tumors is still incomplete. Inflammation plays a vital role in cancer cell survival, metastases, and drug resistance, and the inflammatory protein inducible nitric oxide synthase (NOS2) is emerging as an important player in cancer progression. NOS2 protein is present in about 70% of human breast tumors, and correlates with poor patient survival in the estrogen receptor-negative (ER-) patients. Despite its common expression in tumors, basal NOS2 is typically undetectable in vitro. We examined how various factors and incubation conditions commonly associated with the tumor microenvironment influence NOS2 levels. NOS2 induction was achieved using various stimulants including hypoxia, serum starvation, and different cytokines, including IFN-g. Cell survival factors like tissue inhibitor matrix metalloproteinase 1 (TIMP1) and phosphorylation of AKT were NOS2-induced. Other downstream targets of nitric oxide were found to be regulated by NOS2, including S100A8, IL-6, IL-8 and HIF-1a. The results link inflammation and stress-related mechanisms to NOS2 induction in breast cancer, and its pro-survival signaling that promotes disease progression.

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