Abstract 608: Targeting the estrogen pathway in a male mouse model of lung tumor prevention

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA A hormonal role in the pathology of lung cancer is well documented. We have shown that the aromatase inhibitor anastrozole and the anti-estrogen fulvestrant effectively inhibited tobacco carcinogen-induced lung tumorigenesis in a female mouse model of lung cancer prevention. Additionally, we have shown that inflammatory cells that infiltrate the lungs in response to carcinogens may be a source of estrogen synthesis, and have confirmed aromatase and estrogen receptor expression in a pure macrophage population of differentiated THP-1 cells. These results suggest that targeting the estrogen pathway may be beneficial for both treatment and prevention of lung cancer. There is no sex difference in expression of estrogen-related markers or in relation of these markers to survival in lung cancer patients, suggesting that both men and women may benefit from hormonal therapy. We hypothesized that aromatase activity is a factor in lung cancer development regardless of sex. Since testosterone can serve as an estrogen precursor, we determined whether blocking estrogen action is a feasible lung tumor prevention strategy in male mice. To standardize the amount of estrogen in each animal, orchiectomized male mice were utilized and exogenous testosterone was administered via slow release pellets or daily androstendione injections. Under these conditions, testosterone or androstendione is converted to estrogen through aromatase. The tobacco carcinogen NNK (24mg) was administered in weeks 1-4 followed by a holding period for preneoplasia development. Placebo or anastrozole (0.1mg/kg; p.o. daily) treatment was administered in weeks 9-21. Treatment group (10-11 mice per group) differences were assessed by Poisson regression for number of tumors, and by linear mixed models for tumor size. Anastrozole inhibited the mean number of NNK induced lung tumors per animal by 23% in orchiectomized male mice without hormonal supplementation (placebo treatment mean= 11; range= 8-13 vs anastrozole mean= 8; range= 6-10; p=0.11), by 62.5% in mice supplemented with testosterone (placebo treatment mean= 8; range= 6-11 vs anastrozole mean= 3; range= 2-4; p<0.001) and by 55% in mice supplemented with androstendione (placebo treatment mean= 12, range= 9-16 vs anastrozole mean= 5; range= 4-7; p<0.001). In intact male mice with no hormonal manipulation, anastrozole inhibited lung tumor formation by 33% (p=0.001). Fulvestrant also showed a significant decrease in lung tumors regardless of hormonal status. Tumor number was decreased in general by testosterone suggesting that testosterone may have an inhibitory effect on lung tumor formation. Tumor size was also decreased by anastrozole and fulvestrant under all experimental conditions. Tumor Ki67 and serum β-estradiol levels at sacrifice were significantly decreased by anastrozole. These results suggest that hormonal therapies may benefit male lung cancer patients. Supported by P50CA090440 and the Lung Cancer Research Foundation. Citation Format: Laura P. Stabile, Mary E. Rothstein, Brenda F. Kurland, Diana Cunningham, Matthew Orlowski, Jill M. Siegfried. Targeting the estrogen pathway in a male mouse model of lung tumor prevention. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 608. doi:10.1158/1538-7445.AM2014-608