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Carcinogenesis Advance Access published online on September 11, 2009
Carcinogenesis, doi:10.1093/carcin/bgp203
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Pro-survival of estrogen receptor-negative breast cancer cells is regulated by a BLT2-reactive oxygen species-linked signaling pathway

Jung-A Choi, Jin-Wook Lee, Hyunju Kim, Eun-Young Kim, Ji-Min Seo, Jesang Ko and Jae-Hong Kim{dagger}

School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea

To whom correspondence should be addressed. School of Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk-gu, Seoul, 136-701, Korea, Tel: 82-2-3290-3452 Fax: 82-2-927-9028 E-mail: jhongkim{at}korea.ac.kr

Leukotriene B4 is an inflammatory mediator with potent biological activities in the pathogenesis of many inflammatory diseases. In the present study, we found that expression of BLT2, a low-affinity leukotriene B4 receptor, is significantly up-regulated in breast cancer cells. In addition, we observed that inhibition of BLT2 by a specific antagonist, LY255283, or by siBLT2 RNA interference caused dramatic apoptotic cell death in breast cancer cells, especially in the estrogen receptor (ER)-negative MDA-MB-468 and MDA-MB-453 cells, suggesting a role for BLT2 in survival of these breast cancer cells. In an approach to understand the downstream mechanism by which BLT2 mediates the potential pro-survival signaling, we found that the elevated ROS generation is associated with BLT2-mediated survival. Expression of Nox1, a member of the NADPH oxidase family, is also highly up-regulated in a BLT2-dependent manner in these breast cancer cells, suggesting that ‘Nox1-derived ROS’ lie downstream of BLT2. Consistent with the proposed role of ‘Nox1-ROS’ in pro-survival signaling, knock-down of Nox1 with siNox1 or treatment with a ROS scavenging agent caused dramatic apoptotic death in these breast cancer cells. Taken together, our results demonstrate, for the first time, that the ‘BLT2-Nox1-ROS’-linked cascade is involved in the pro-survival signaling, especially in ER-negative breast cancer cells.

Key Words: leukotriene B4 receptor BLT2 • ROS • survival • breast cancer

Received April 15, 2009; revised July 29, 2009; accepted August 1, 2009.


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