In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 2923-2923
Abstract:
Lung cancer is the most common cause of cancer mortality in male and female patients in the US. Non-small cell lung cancer (NSCLC) accounts for more than 85% of lung cancers. Standard initial chemotherapy for patients with advanced NSCLC is a platinum-based regimen, with data showing that these therapies elicit a modest improvement in patient survival. However, a major limitation to cisplatin therapy is development of drug resistance, leading to cancer progression and reduced patient survival. Cisplatin acts by interacting with DNA to form adducts that, in turn, activate signaling pathways for cell death (apoptosis). DNA damage-mediated apoptotic signals, however, can be blocked, and the resistance that ensues is a major drawback of cisplatin therapy. Resistance mechanisms, such as increased DNA adduct repair, may be modulated by interactions with other signaling pathways for cell survival, and emerging data suggest that estrogens may play a role in this process. To understand how estrogens modulate cisplatin resistance in vitro, we used two models of human NSCLC, A549 and H23 cells, that proliferate in response to estradiol-17β (E2) and express estrogen receptors and aromatase (enzyme that produces estrogens locally). Cisplatin markedly reduces tumor cell growth and enhances apoptosis in both models. However, the antitumor action of cisplatin is significantly blocked when cells are treated with estrogen in vitro. Using qRT-PCR and Western immunoblot analysis of excision repair cross-complementing-1 (ERCC1) protein (repairs cisplatin-induced DNA damage), we find that ERCC1 mRNA and protein levels are significantly increased in the presence of estrogen, thereby suggesting a potential mechanism for estrogen-induced cisplatin resistance. Analyses of the 5’-regulatory region of the human ERCC1 gene revealed putative half-estrogen responsive elements in close proximity with sp1 and AP1 sites. Chromatin immunoprecipitation assays showed binding of estrogen receptors to these promoter sites. Furthermore, treatment of human NSCLC xenografts in vivo with an aromatase inhibitor (exemestane) alone or combined with standard cisplatin chemotherapy elicits a significant reduction in tumor progression as compared to paired controls. A new strategy to block NSCLC progression may be use of cisplatin with simultaneous suppression of estrogen signaling (such as use of aromatase inhibitors). [Supported by NIH Lung Cancer SPORE, National Lung Cancer Partnership and Stiles Program funds]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2923.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-2923
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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