From Sanja Dacic and colleagues: Prevention of Tobacco Carcinogen-Induced Lung Cancer in Female Mice Using Anti-Estrogens

http://www.ncbi.nlm.nih.gov/pubmed/22859269

Carcinogenesis. 2012 Aug 2. [Epub ahead of print]

Prevention of Tobacco Carcinogen-Induced Lung Cancer in Female Mice Using Anti-Estrogens.

Stabile LP, Rothstein ME, Cunningham DE, Land SR, Dacic S, Keohavong P, Siegfried JM.

Source

Department of Pharmacology & Chemical Biology, University of Pittsburgh and University of Pittsburgh Cancer Institute.

Abstract

Increasing evidence shows that estrogens are involved in lung cancer proliferation and progression, and most human lung tumors express estrogen receptor β (ERβ) as well as aromatase. To determine if the aromatase inhibitor anastrozole prevents development of lung tumors induced by a tobacco carcinogen, alone or in combination with the ER antagonist fulvestrant, ovariectomized female mice received treatments with the tobacco carcinogen NNK along with daily supplements of androstenedione, the substrate for aromatase. Placebo, anastrozole and/or fulvestrant were administered in both an initiation and a promotion protocol of lung tumorigenesis. The combination of fulvestrant and anastrozole given during NNK exposure resulted in significantly fewer NNK-induced lung tumors (mean=0.5) compared to placebo (mean=4.6, P<0.001), fulvestrant alone (mean=3.4, P<0.001) or anastrozole alone (mean=2.8, P=0.002). A significantly lower Ki67 cell proliferation index was also observed compared to single agent and control treatment groups. Beginning anti-estrogen treatment after NNK exposure, when preneoplastic lesions had already formed, also yielded maximum anti-tumor effects with the combination. Aromatase expression was found mainly in macrophages infiltrating preneoplastic and tumorous areas of the lungs, while ERβ was found in both macrophages and tumor cells. Anti-estrogens, especially in combination, effectively inhibited tobacco carcinogen-induced murine lung tumorigenesis, and may have application for lung cancer prevention. An important source of estrogen synthesis may be inflammatory cells that infiltrate the lungs in response to carcinogens, beginning early in the carcinogenesis process. ERβ expressed by inflammatory and neoplastic epithelial cells in the lung may signal in response to local estrogen production.