Journal Article

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

in Carcinogenesis

Volume 31, issue 4, pages 543-551
Published in print April 2010 | ISSN: 0143-3334
Published online September 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp203
Pro-survival of estrogen receptor-negative breast cancer cells is regulated by a BLT2–reactive oxygen species-linked signaling pathway

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Leukotriene B4 (LTB4) 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 LTB4 receptor, is significantly upregulated 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 reactive oxygen species (ROS) generation is associated with BLT2-mediated survival. Expression of Nox1, a member of the NADPH oxidase family, is also highly upregulated 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, knockdown 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.

Journal Article.  6811 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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